HIV-1 Protease Inhibitors as Antiretroviral Agents
Sergei V. Gulnik
Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA
Search for more papers by this authorElena Afonina
Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA
Search for more papers by this authorMichael Eissenstat
Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA
Search for more papers by this authorSergei V. Gulnik
Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA
Search for more papers by this authorElena Afonina
Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA
Search for more papers by this authorMichael Eissenstat
Sequoia Pharmaceuticals, Inc., Gaithersburg, Maryland, USA
Search for more papers by this authorChuang Lu
Department of DMPK, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, USA
Search for more papers by this authorAlbert P. Li
In Vitro ADMET Laboratories, Columbia, Maryland, USA
Search for more papers by this authorSummary
This chapter contains sections titled:
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Introduction
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HIV PR as an Antiviral Target
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Inhibitors of HIV PR
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Concluding Remarks
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Acronyms
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Acknowledgments
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References
REFERENCES
- Acosta EP, Kakuda TN, Brundage RC, Anderson PL, Fletcher CV. Pharmacodynamics of human immunodeficiency virus type 1 protease inhibitors. Clin Infect Dis 2000; 30(Suppl 2): S151–S159.
- Altman MD, Ali A, Kumar Reddy GS, Nalam MN, Anjum SG, Cao H, Chellappan S, Kairys V, Fernandes MX, Gilson MK, Schiffer CA, Rana TM, Tidor B. HIV-1 Protease inhibitors from inverse design in the substrate envelope exhibit subnanomolar binding to drug-resistant variants. J Am Chem Soc 2008; 130: 6099–6113.
- Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene 2005; 24: 7455–7464.
- Autar RS, Wit FW, Sankote J, Sutthichom D, Kimenai E, Hassink E, Hill A, Cooper DA, Phanuphak P, Lange JM, Burger DM, Ruxrungtham K. Ketoconazole is inferior to ritonavir as an alternative booster for saquinavir in a once daily regimen in Thai HIV-1 infected patients. AIDS 2007; 21: 1535–1539.
- Baldwin ET, Bhat TN, Liu B, Pattabiraman N, Erickson JW. Structural basis of drug resistance for the V82A mutant of HIV-1 proteinase. Nat Struct Biol 1995; 2: 244–249.
- Bannwarth L, Reboud-Ravaux M. An alternative strategy for inhibiting multidrug-resistant mutants of the dimeric HIV-1 protease by targeting the subunit interface. Biochem Soc Trans 2007; 35: 551–554.
- Barbaro G. Highly active antiretroviral therapy-associated metabolic syndrome: pathogenesis and cardiovascular risk. Am J Ther 2006; 13: 248–260.
- Barrios A, Rendon AL, Gallego O, Martin-Carbonero L, Valer L, Rios P, Maida I, Garcia-Benayas T, Jimenez-Nacher I, Gonzalez-Lahoz J, Soriano V. Predictors of virological response to atazanavir in protease inhibitor-experienced patients. HIV Clin Trials 2004; 5: 201–205.
- Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, Luboinski J, Laville M, Maachi M, Girard PM, Rozenbaum W, Levan P, Capeau J. Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 2002; 359: 1026–1031.
- Beaulieu PL, Anderson PC, Cameron DR, Croteau G, Gorys V, Grand-Maitre C, Lamarre D, Liard F, Paris W, Plamondon L, Soucy F, Thibeault D, Wernic D, Yoakim C, Pav S, Tong L. 2′,6′-Dimethylphenoxyacetyl: a new achiral high affinity P(3)-P(2) ligand for peptidomimetic-based HIV protease inhibitors. J Med Chem 2000; 43: 1094–1108.
- Becker SL. The role of pharmacological enhancement in protease inhibitor-based highly active antiretroviral therapy. Expert Opin Investig Drugs 2003; 12: 401–412.
- Ben-Romano R, Rudich A, Torok D, Vanounou S, Riesenberg K, Schlaeffer F, Klip A, Bashan N. Agent and cell-type specificity in the induction of insulin resistance by HIV protease inhibitors. AIDS 2003; 17: 23–32.
- Ben-Romano R, Rudich A, Tirosh A, Potashnik R, Sasaoka T, Riesenberg K, Schlaeffer F, Bashan N. Nelfinavir-induced insulin resistance is associated with impaired plasma membrane recruitment of the PI 3-kinase effectors Akt/PKB and PKC-zeta. Diabetologia 2004; 47: 1107–1117.
- Bold G, Fassler A, Capraro HG, Cozens R, Klimkait T, Lazdins J, Mestan J, Poncioni B, Rosel J, Stover D, Tintelnot-Blomley M, Acemoglu F, Beck W, Boss E, Eschbach M, Hurlimann T, Masso E, Roussel S, Ucci-Stoll K, Wyss D, Lang M. New azadipeptide analogues as potent and orally absorbed HIV-1 protease inhibitors: candidates for clinical development. J Med Chem 1998; 41: 3387–3401.
- Bonomi M, Gervasio FL, Tiana G, Provasi D, Broglia RA, Parrinello M. Insight into the folding inhibition of the HIV-1 protease by a small peptide. Biophys J 2007; 93: 2813–2821.
- Braun PWH, Hoffman D, Daumer M, Ehret R, Korn K, Thiele B, Burg T, Sturmer M, Wiesmann F, Kaiser R. Clinically relevant resensitization of PI saquinavir and atazanavir by L76V in multidrug-resistant HIV-1-infected patients. Antiviral Therapy 2007; 12: abstract 129.
- Brik A, Wong CH. HIV-1 protease: mechanism and drug discovery. Org Biomol Chem 2003; 1: 5–14.
- Broglia RA, Provasi D, Vasile F, Ottolina G, Longhi R, Tiana G. A folding inhibitor of the HIV-1 protease. Proteins 2006; 62: 928–933.
- Broglia RA, Tiana G, Sutto L, Provasi D, Perelli V. Low-throughput model design of protein folding inhibitors. Proteins 2007; 67: 469–478.
- Broglia R, Levy Y, Tiana G. HIV-1 protease folding and the design of drugs which do not create resistance. Curr Opin Struct Biol 2008; 18: 60–66.
- Callebaut C, Stray K, Tsai L, Xu L, He GX, Mulato A, Priskich T, Parkin N, Lee W, Cihlar T. Profile of GS-8374, a Novel Phosphonate-containing HIV PI: in vitro antiretroviral activity, toxicity, and resistance. Abstract 491. CROI, Los Angeles, 2007.
- Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeau J. The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes 2001; 50: 1378–1388.
- Carr A. HIV protease inhibitor-related lipodystrophy syndrome. Clin Infect Dis 2000; 30(Suppl 2): S135–S142.
- Chellappan S, Kiran Kumar Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Kairys V, Fernandes MX, Altman MD, Tidor B, Rana TM, Schiffer CA, Gilson MK. Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 2007; 69: 298–313.
- Chen Z, Li Y, Schock HB, Hall D, Chen E, Kuo LC. Three-dimensional structure of a mutant HIV-1 protease displaying cross-resistance to all protease inhibitors in clinical trials. J Biol Chem 1995; 270: 21433–21436.
- Cheng YS, Yin FH, Foundling S, Blomstrom D, Kettner CA. Stability and activity of human immunodeficiency virus protease: comparison of the natural dimer with a homologous, single-chain tethered dimer. Proc Natl Acad Sci USA 1990; 87: 9660–9664.
- Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB 3rd, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 2001; 292: 1728–1731.
- Choy N, Lee CS, Park C, Choi H, Son Y-C, Moon KY, Jung WH, Kim CR, Yoon H, Kim SC. Irreversible and orally absorbable HIV-1 protease inactivator. Korean J Med Chem 1996; 6: 309–316.
- Cihlar T, He GX, Liu X, Chen JM, Hatada M, Swaminathan S, McDermott MJ, Yang ZY, Mulato AS, Chen X, Leavitt SA, Stray KM, Lee WA. Suppression of HIV-1 protease inhibitor resistance by phosphonate-mediated solvent anchoring. J Mol Biol 2006; 363: 635–647.
- Clemente JC, Moose RE, Hemrajani R, Whitford LR, Govindasamy L, Reutzel R, McKenna R, Agbandje-McKenna M, Goodenow MM, Dunn BM. Comparing the accumulation of active- and nonactive-site mutations in the HIV-1 protease. Biochemistry 2004; 43: 12141–12151.
- Clemente JC, Coman RM, Thiaville MM, Janka LK, Jeung JA, Nukoolkarn S, Govindasamy L, Agbandje-McKenna M, McKenna R, Leelamanit W, Goodenow MM, Dunn BM. Analysis of HIV-1 CRF_01 A/E protease inhibitor resistance: structural determinants for maintaining sensitivity and developing resistance to atazanavir. Biochemistry 2006; 45: 5468–5477.
- Collins JR, Burt SK, Erickson JW. Flap opening in HIV-1 protease simulated by “activated” molecular dynamics. Nat Struct Biol 1995; 2: 334–338.
- Condra JH, Schleif WA, Blahy OM, Gabryelski LJ, Graham DJ, Quintero JC, Rhodes A, Robbins HL, Roth E, Shivaprakash M, et al. In vivo emergence of HIV-1 variants resistant to multiple protease inhibitors. Nature 1995; 374: 569–571.
- Copeland RA. Tight binding inhibition. In: Evaluation of Enzyme Inhibitors in Drug Discovery. Hoboken, NJ: John Wiley & Sons, 2005, pp. 178–213.
- Copeland RA, Pompliano DL, Meek TD. Drug-target residence time and its implications for lead optimization. Nat Rev Drug Discovery 2006; 5: 730–739.
- Craig JC, Duncan IB, Hockley D, Grief C, Roberts NA, Mills JS. Antiviral properties of Ro 31-8959, an inhibitor of human immunodeficiency virus (HIV) proteinase. Antiviral Res 1991; 16: 295–305.
- Culm-Merdek KE, von Moltke LL, Gan L, Horan KA, Reynolds R, Harmatz JS, Court MH, Greenblatt DJ. Effect of extended exposure to grapefruit juice on cytochrome P450 3A activity in humans: comparison with ritonavir. Clin Pharmacol Ther 2006; 79: 243–254.
- Dandache S, Sevigny G, Yelle J, Stranix BR, Parkin N, Schapiro JM, Wainberg MA, Wu JJ. In vitro antiviral activity and cross-resistance profile of PL-100, a novel protease inhibitor of human immunodeficiency virus type 1. Antimicrob Agents Chemother 2007; 51: 4036–4043.
- Darke PL, Jordan SP, Hall DL, Zugay JA, Shafer JA, Kuo LC. Dissociation and association of the HIV-1 protease dimer subunits: equilibria and rates. Biochemistry 1994; 33: 98–105.
- Das A, Prashar V, Mahale S, Serre L, Ferrer JL, Hosur MV. Crystal structure of HIV-1 protease in situ product complex and observation of a low-barrier hydrogen bond between catalytic aspartates. Proc Natl Acad Sci USA 2006; 103: 18464–18469.
- Davies DR. The structure and function of the aspartic proteinases. Annu Rev Biophys Biophys Chem 1990; 19: 189–215.
- De Meyer S, Azijn H, Surleraux D, Jochmans D, Tahri A, Pauwels R, Wigerinck P, de Bethune MP. TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates. Antimicrob Agents Chemother 2005; 49: 2314–2321.
- De Meyer S, Vangeneugden T, van Baelen B, de Paepe E, van Marck H, Picchio G, Lefebvre E, de Bethune MP. Resistance profile of darunavir: combined 24-week results from the POWER trials. AIDS Res Hum Retroviruses 2008; 24: 379–388.
- Degawa-Yamauchi M, Bovenkerk JE, Juliar BE, Watson W, Kerr K, Jones R, Zhu Q, Considine RV. Serum resistin (FIZZ3) protein is increased in obese humans. J Clin Endocrinol Metab 2003; 88: 5452–5455.
- Desai MC, Hong AY, Liu H, Xu L, Vivian RW. Preparation of peptidomimetics as modulators of pharmacokinetic properties of therapeutics by inhibiting cytochrome P450 monooxygenase. WO 2008010921, 2008.
- DHHS. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and-adolescents, 2008, pp. 1–139.
- Dierynck I, De Wit M, Gustin E, Keuleers I, Vandersmissen J, Hallenberger S, Hertogs K. Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. J Virol 2007; 81: 13845–13851.
- Dixit V, Hariparsad N, Li F, Desai P, Thummel KE, Unadkat JD. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Dispos 2007; 35: 1853–1859.
- Dorsey BD, Levin RB, McDaniel SL, Vacca JP, Guare JP, Darke PL, Zugay JA, Emini EA, Schleif WA, Quintero JC, et al. L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. J Med Chem 1994; 37: 3443–3451.
- Dowell P, Flexner C, Kwiterovich PO, Lane MD. Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem 2000; 275: 41325–41332.
- Doyon L, Croteau G, Thibeault D, Poulin F, Pilote L, Lamarre D. Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors. J Virol 1996; 70: 3763–3769.
- Drewe J, Gutmann H, Fricker G, Torok M, Beglinger C, Huwyler J. HIV protease inhibitor ritonavir: a more potent inhibitor of P-glycoprotein than the cyclosporine analog SDZ PSC 833. Biochem Pharmacol 1999; 57: 1147–1152.
- Dunn BM. Structure and mechanism of the pepsin-like family of aspartic peptidases. Chem Rev 2002; 102: 4431–4458.
- Dunn BM, Gustchina A, Wlodawer A, Kay J. Subsite preferences of retroviral proteinases. Methods Enzymol 1994; 241: 254–278.
- Eissenstat M, Duan D. Benzofuransulfonamide derivatives, processes for preparing them, pharmaceutical compositions containing them, and their use as inhibitors of cytochrome P 450. WO 2008022345, 2008.
- Eissenstat M, Guerassina T. Preparation of diamino-mono-ol dipeptide isostere core based resistance-repellent retroviral protease inhibitors. WO 2005087728, 2005.
- Eissenstat M, Delahanty G, Topin A, Rajendran GR. Preparation of heterocyclyl sulfonylaminobenzylhydroxypropylcarbamates as HIV protease inhibitors. WO 2005110428, 2005.
- Elston RS, Hall D, Shapiro J, Bethell R, Kohlbrenner V, Mayers D. Deselection of the I50V mutations occurs in the clinical isolates during aptivus/r (tipranavir/ritonavir)-based therapy. Antiviral Therapy 2006; 11:abstract 92.
- Erickson J, Neidhart DJ, VanDrie J, Kempf DJ, Wang XC, Norbeck DW, Plattner JJ, Rittenhouse JW, Turon M, Wideburg N, et al. Design, activity, and 2.8 A crystal structure of a C2 symmetric inhibitor complexed to HIV-1 protease. Science 1990; 249: 527–533.
- Erickson JW. The not-so-great escape. Nat Struct Biol 1995; 2: 523–529.
- Erickson JW, Burt SK. Structural mechanisms of HIV drug resistance. Annu Rev Pharmacol Toxicol 1996; 36: 545–571.
- Erickson JW, Gulnik SV, Ghosh AK, Hussain KA. Multidrug-resistant retroviral protease inhibitors and associated methods. WO 9967254, 1999.
- Erickson JW, Eissenstat M, Silva A, Gulnik S. Broad spectrum microbial and neoplasmic protein inhibitors. WO 2003057173, 2003.
- Erickson JW, Eissenstat M, Silva AM, Afonina E, Gulnik S. Design and crystal structure of SPI-256: an experimental HIV protease inhibitor with a high genetic barrier to resistance. In: ICAAC, Washington, DC, Abstract 1266, 2008.
- Erickson-Viitanen S, Klabe RM, Cawood PG, O'Neal PL, Meek JL. Potency and selectivity of inhibition of human immunodeficiency virus protease by a small nonpeptide cyclic urea, DMP 323. Antimicrob Agents Chemother 1994; 38: 1628–1634.
- Ernest CS, 2nd, Hall SD, Jones DR. Mechanism-based inactivation of CYP3A by HIV protease inhibitors. J Pharmacol Exp Ther 2005; 312: 583–591.
- Fassler A, Bold G, Capraro HG, Cozens R, Mestan J, Poncioni B, Rosel J, Tintelnot-Blomley M, Lang M. Aza-peptide analogs as potent human immunodeficiency virus type-1 protease inhibitors with oral bioavailability. J Med Chem 1996; 39: 3203–3216.
- Fellay J, Marzolini C, Decosterd L, Golay KP, Baumann P, Buclin T, Telenti A, Eap CB. Variations of CYP3A activity induced by antiretroviral treatment in HIV-1 infected patients. Eur J Clin Pharmacol 2005; 60: 865–873.
- Fichtenbaum CJ, Gerber JG. Interactions between antiretroviral drugs and drugs used for the therapy of the metabolic complications encountered during HIV infection. Clin Pharmacokinet 2002; 41: 1195–1211.
- Flentge CA, Randolph JT, Huang PP, Klein LL, Marsh KC, Harlan JE, Kempf DJ. Synthesis and evaluation of bifunctional inhibitors of cytochrome P-450 3A. Abstracts of Papers, 236th ACS National Meeting, Philadelphia, United States, August 17–21, 2008, MEDI-299.
- Foisy MM, Yakiwchuk EM, Hughes CA. Induction effects of ritonavir: implications for drug interactions. Ann Pharmacother 2008; 42: 1048–1059.
- Ford J, Meaden ER, Hoggard PG, Dalton M, Newton P, Williams I, Khoo SH, Back DJ. Effect of protease inhibitor-containing regimens on lymphocyte multidrug resistance transporter expression. J Antimicrob Chemother 2003; 52: 354–358.
- Ford SL, Reddy YS, Anderson MT, Murray SC, Fernandez P, Stein DS, Johnson MA. Single-dose safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus protease inhibitor. Antimicrob Agents Chemother 2006; 50: 2201–2206.
- Freedberg DI, Ishima R, Jacob J, Wang YX, Kustanovich I, Louis JM, Torchia DA. Rapid structural fluctuations of the free HIV protease flaps in solution: relationship to crystal structures and comparison with predictions of dynamics calculations. Protein Sci 2002; 11: 221–232.
- Freskos JN, Bertenshaw DE, Getman DP, Heintz RM, Mischke BV, Blystone LW, Bryant ML, Funckes-Shippy C, Houseman KA, et al. (Hydroxyethyl)sulfonamide HIV-1 protease inhibitors: identification of the 2-methylbenzoyl moiety at P-2. Bioorg Med Chem Lett 1996; 6: 445–450.
- Frutos S, Rodriguez-Mias RA, Madurga S, Collinet B, Reboud-Ravaux M, Ludevid D, Giralt E. Disruption of the HIV-1 protease dimer with interface peptides: structural studies using NMR spectroscopy combined with [2-(13)C]-Trp selective labeling. Biopolymers 2007; 88: 164–173.
- Furfine ES, Baker CT, Hale MR, Reynolds DJ, Salisbury JA, Searle AD, Studenberg SD, Todd D, Tung RD, Spaltenstein A. Preclinical pharmacology and pharmacokinetics of GW433908, a water-soluble prodrug of the human immunodeficiency virus protease inhibitor amprenavir. Antimicrob Agents Chemother 2004; 48: 791–798.
- Gabriely I, Ma XH, Yang XM, Atzmon G, Rajala MW, Berg AH, Scherer P, Rossetti L, Barzilai N. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes 2002; 51: 2951–2958.
- Gallant JE. Protease-inhibitor boosting in the treatment-experienced patient. AIDS Rev 2004; 6: 226–233.
- Gatanaga H, Suzuki Y, Tsang H, Yoshimura K, Kavlick MF, Nagashima K, Gorelick RJ, Mardy S, Tang C, Summers MF, Mitsuya H. Amino acid substitutions in Gag protein at non-cleavage sites are indispensable for the development of a high multitude of HIV-1 resistance against protease inhibitors. J Biol Chem 2002; 277: 5952–5961.
- Geese WJ, Ranade K. Polymorphisms of human resistin gene and uses for identifying HIV-1 protease inhibitors with reduced metabolic affects. US 2008004209, 2008.
- Ghosh AK, Thompson WJ, McKee SP, Duong TT, Lyle TA, Chen JC, Darke PL, Zugay JA, Emini EA, Schleif WA, et al. 3-Tetrahydrofuran and pyran urethanes as high-affinity P2-ligands for HIV-1 protease inhibitors. J Med Chem 1993; 36: 292–294.
- Ghosh AK, Thompson WJ, Fitzgerald PM, Culberson JC, Axel MG, McKee SP, Huff JR, Anderson PS. Structure-based design of HIV-1 protease inhibitors: replacement of two amides and a 10 pi-aromatic system by a fused bis-tetrahydrofuran. J Med Chem 1994; 37: 2506–2508.
- Ghosh AK, Kincaid JF, Walters DE, Chen Y, Chaudhuri NC, Thompson WJ, Culberson C, Fitzgerald PM, Lee HY, McKee SP, Munson PM, Duong TT, Darke PL, Zugay JA, Schleif WA, Axel MG, Lin J, Huff JR. Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation. J Med Chem 1996; 39: 3278–3290.
- Ghosh AK, Kincaid JF, Cho W, Walters DE, Krishnan K, Hussain KA, Koo Y, Cho H, Rudall C, Holland L, Buthod J. Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. Bioorg Med Chem Lett 1998; 8: 687–690.
- Ghosh AK, Ramu Sridhar P, Kumaragurubaran N, Koh Y, Weber IT, Mitsuya H. Bis-tetrahydrofuran: a privileged ligand for darunavir and a new generation of hiv protease inhibitors that combat drug resistance. Chem Med Chem 2006a; 1: 939–950.
- Ghosh AK, Sridhar PR, Leshchenko S, Hussain AK, Li J, Kovalevsky AY, Walters DE, Wedekind JE, Grum-Tokars V, Das D, Koh Y, Maeda K, Gatanaga H, Weber IT, Mitsuya H. Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance. J Med Chem 2006b; 49: 5252–5261.
- Ghosh AK, Dawson ZL, Mitsuya H. Darunavir, a conceptually new HIV-1 protease inhibitor for the treatment of drug-resistant HIV. Bioorg Med Chem 2007; 15: 7576–7580.
- Ghosh AK, Chapsal BD, Weber IT, Mitsuya H. Design of HIV Protease Inhibitors Targeting Protein Backbone: An Effective Strategy for Combating Drug Resistance. Acc Chem Res 2008; 41: 78–86.
- Gianotti N, Soria A, Lazzarin A. Antiviral activity and clinical efficacy of atazanavir in HIV-1-infected patients: a review. New Microbiol 2007; 30: 79–88.
- Gong YF, Robinson BS, Rose RE, Deminie C, Spicer TP, Stock D, Colonno RJ, Lin PF. In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother 2000; 44: 2319–2326.
- Gonzalez de Requena D, Gallego O, Valer L, Jimenez-Nacher I, Soriano V. prediction of virological response to lopinavir/ritonavir using the genotypic inhibitory quotient. AIDS Res Hum Retroviruses 2004; 20: 275–278.
- Granfors MT, Wang JS, Kajosaari LI, Laitila J, Neuvonen PJ, Backman JT. Differential inhibition of cytochrome P450 3A4, 3A5 and 3A7 by five human immunodeficiency virus (HIV) protease inhibitors in vitro. Basic Clin Pharmacol Toxicol 2006; 98: 79–85.
- Grant SK, Deckman IC, Culp JS, Minnich MD, Brooks IS, Hensley P, Debouck C, Meek TD. Use of protein unfolding studies to determine the conformational and dimeric stabilities of HIV-1 and SIV proteases. Biochemistry 1992; 31: 9491–9501.
- Greenblatt DJ, von Moltke LL, Daily JP, Harmatz JS, Shader RI. Extensive impairment of triazolam and alprazolam clearance by short-term low-dose ritonavir: the clinical dilemma of concurrent inhibition and induction. J Clin Psychopharmacol 1999; 19: 293–296.
- Griffiths JT, Phylip LH, Konvalinka J, Strop P, Gustchina A, Wlodawer A, Davenport RJ, Briggs R, Dunn BM, Kay J. Different requirements for productive interaction between the active site of HIV-1 proteinase and substrates containing -hydrophobic*hydrophobic- or -aromatic*pro- cleavage sites. Biochemistry 1992; 31: 5193–5200.
- Gulnik SV, Eissenstat M. Approaches to the design of HIV protease inhibitors with improved resistance profiles. Curr Opin HIV AIDS 2008; 3: 633–641.
- Gulnik SV, Suvorov LI, Liu B, Yu B, Anderson B, Mitsuya H, Erickson JW. Kinetic characterization and cross-resistance patterns of HIV-1 protease mutants selected under drug pressure. Biochemistry 1995; 34: 9282–9287.
- Gulnik S, Erickson JW, Xie D. HIV protease: enzyme function and drug resistance. Vitam Horm 2000; 58: 213–256.
- Gupta V, Samuleson CG, Su S, Chen TC. Nelfinavir potentiation of imatinib cytotoxicity in meningioma cells via survivin inhibition. Neurosurg Focus 2007; 23: E9.
- Gutmann H, Fricker G, Drewe J, Toeroek M, Miller DS. Interactions of HIV protease inhibitors with ATP-dependent drug export proteins. Mol Pharmacol 1999; 56: 383–389.
- Haas DW, Arathoon E, Thompson MA, de Jesus Pedro R, Gallant JE, Uip DE, Currier J, Noriega LM, Lewi DS, Uribe P, Benetucci L, Cahn P, Paar D, White AC Jr, Collier AC, Ramirez-Ronda CH, Harvey C, Chung MO, Mehrotra D, Chodakewitz J, Nguyen BY. Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. AIDS 2000; 14: 1973–1978.
- Hanlon MH, Porter DJ, Furfine ES, Spaltenstein A, Carter HL, Danger D, Shu AY, Kaldor IW, Miller JF, Samano VA. Inhibition of wild-type and mutant human immunodeficiency virus type 1 proteases by GW0385 and other arylsulfonamides. Biochemistry 2004; 43: 14500–14507.
- Haubrich RH. Resistance and replication capacity assays: clinical utility and interpretation. Top HIV Med 2004; 12: 52–56.
- Hazen R, Harvey R, Ferris R, Craig C, Yates P, Griffin P, Miller J, Kaldor I, Ray J, Samano V, Furfine E, Spaltenstein A, Hale M, Tung R, St Clair M, Hanlon M, Boone L. In vitro antiviral activity of the novel, tyrosyl-based human immunodeficiency virus (HIV) type 1 protease inhibitor brecanavir (GW640385) in combination with other antiretrovirals and against a panel of protease inhibitor-resistant HIV. Antimicrob Agents Chemother 2007; 51: 3147–3154.
- Hertel J, Struthers H, Horj CB, Hruz PW. A structural basis for the acute effects of HIV protease inhibitors on GLUT4 intrinsic activity. J Biol Chem 2004; 279: 55147–55152.
- Hertogs K, Bloor S, Kemp SD, Van den Eynde C, Alcorn TM, Pauwels R, Van Houtte M, Staszewski S, Miller V, Larder BA. Phenotypic and genotypic analysis of clinical HIV-1 isolates reveals extensive protease inhibitor cross-resistance: a survey of over 6000 samples. AIDS 2000; 14: 1203–1210.
- Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 2002; 420: 333–336.
- Hodge CN, Aldrich PE, Bacheler LT, Chang CH, Eyermann CJ, Garber S, Grubb M, Jackson DA, Jadhav PK, Korant B, Lam PY, Maurin MB, Meek JL, Otto MJ, Rayner MM, Reid C, Sharpe TR, Shum L, Winslow DL, Erickson-Viitanen S. Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. Chem Biol 1996; 3: 301–314.
- Hoefnagel JG, Koopmans PP, Burger DM, Schuurman R, Galama JM. Role of the inhibitory quotient in HIV therapy. Antivir Ther 2005; 10: 879–892.
- Hoetelmans RM, Reijers MH, Weverling GJ, ten Kate RW, Wit FW, Mulder JW, Weigel HM, Frissen PH, Roos M, Jurriaans S, Schuitemaker H, de Wolf F, Beijnen JH, Lange JM. The effect of plasma drug concentrations on HIV-1 clearance rate during quadruple drug therapy. AIDS 1998; 12: F111–F115.
- Hong L, Zhang XC, Hartsuck JA, Tang J. Crystal structure of an in vivo HIV-1 protease mutant in complex with saquinavir: insights into the mechanisms of drug resistance. Protein Sci 2000; 9: 1898–1904.
- Hoog SS, Towler EM, Zhao B, Doyle ML, Debouck C, Abdel-Meguid SS. Human immunodeficiency virus protease ligand specificity conferred by residues outside of the active site cavity. Biochemistry 1996; 35: 10279–10286.
- Hornak V, Okur A, Rizzo RC, Simmerling C. HIV-1 protease flaps spontaneously open and reclose in molecular dynamics simulations. Proc Natl Acad Sci USA 2006; 103: 915–920.
- Hornak V, Simmerling C. Targeting structural flexibility in HIV-1 protease inhibitor binding. Drug Discov Today 2007; 12: 132–138.
- Hsu A, Granneman GR, Bertz RJ. Ritonavir. Clinical pharmacokinetics and interactions with other anti-HIV agents. Clin Pharmacokinet 1998; 35: 275–291.
- Hsu A, Isaacson J, Brun S, Bernstein B, Lam W, Bertz R, Foit C, Rynkiewicz K, Richards B, King M, Rode R, Kempf DJ, Granneman GR, Sun E. Pharmacokinetic-pharmacodynamic analysis of lopinavir—ritonavir in combination with efavirenz and two nucleoside reverse transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected patients. Antimicrob Agents Chemother 2003; 47: 350–359.
- Hyland LJ, Tomaszek TA Jr, Meek TD. Human immunodeficiency virus-1 protease. 2. Use of pH rate studies and solvent kinetic isotope effects to elucidate details of chemical mechanism. Biochemistry 1991a; 30: 8454–8463.
- Hyland LJ, Tomaszek TA Jr, Roberts GD, Carr SA, Magaard VW, Bryan HL, Fakhoury SA, Moore ML, Minnich MD, Culp JS, et al. Human immunodeficiency virus-1 protease. 1. Initial velocity studies and kinetic characterization of reaction intermediates by 18O isotope exchange. Biochemistry 1991b; 30: 8441–8453.
- Ikezoe T, Hisatake Y, Takeuchi T, Ohtsuki Y, Yang Y, Said JW, Taguchi H, Koeffler HP. HIV-1 protease inhibitor, ritonavir: a potent inhibitor of CYP3A4, enhanced the anticancer effects of docetaxel in androgen-independent prostate cancer cells in vitro and in vivo. Cancer Res 2004; 64: 7426–7431.
- Ishima R, Freedberg DI, Wang YX, Louis JM, Torchia DA. Flap opening and dimerinterface flexibility in the free and inhibitor-bound HIV protease, and their implications for function. Structure 1999; 7: 1047–1055.
- Ishima R, Torchia DA, Lynch SM, Gronenborn AM, Louis JM. Solution structure of the mature HIV-1 protease monomer: insight into the tertiary fold and stability of a precursor. J Biol Chem 2003; 278: 43311–43319.
- Ishima R, Torchia DA, Louis JM. Mutational and structural studies aimed at characterizing the monomer of HIV-1 protease and its precursor. J Biol Chem 2007; 282: 17190–17199.
- Janneh O, Jones E, Chandler B, Owen A, Khoo SH. Inhibition of P-glycoprotein and multidrug resistance-associated proteins modulates the intracellular concentration of lopinavir in cultured CD4 T cells and primary human lymphocytes. J Antimicrob Chemother 2007; 60: 987–993.
- Johnson VA, Brun-Vezinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, Schapiro JM, Richman DD. Update of the drug resistance mutations in HIV-1: spring 2008. Top HIV Med 2008; 16: 62–68.
- Jordan SP, Zugay J, Darke PL, Kuo LC. Activity and dimerization of human immunodeficiency virus protease as a function of solvent composition and enzyme concentration. J Biol Chem 1992; 267: 20028–20032.
- Kaldor SW, Kalish VJ, Davies JF, 2nd, Shetty BV, Fritz JE, Appelt K, Burgess JA, Campanale KM, Chirgadze NY, Clawson DK, Dressman BA, Hatch SD, Khalil DA, Kosa MB, Lubbehusen PP, Muesing MA, Patick AK, Reich SH, Su KS, Tatlock JH. Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. J Med Chem 1997; 40: 3979–3985.
- Kaletra, prescribing information. In: Physicians' Desk Reference, 62nd ed. Montvale, NJ: Thomson Healthcare Inc., 2008, pp. 456–466.
- Kannisto K, Sutinen J, Korsheninnikova E, Fisher RM, Ehrenborg E, Gertow K, Virkamaki A, Nyman T, Vidal H, Hamsten A, Yki-Jarvinen H. Expression of adipogenic transcription factors, peroxisome proliferator-activated receptor gamma co-activator 1, IL-6 and CD45 in subcutaneous adipose tissue in lipodystrophy associated with highly active antiretroviral therapy. AIDS 2003; 17: 1753–1762.
- Kaplan AH, Zack JA, Knigge M, Paul DA, Kempf DJ, Norbeck DW, Swanstrom R. Partial inhibition of the human immunodeficiency virus type 1 protease results in aberrant virus assembly and the formation of noninfectious particles. J Virol 1993; 67: 4050–4055.
- Kaplan AH, Manchester M, Swanstrom R. The activity of the protease of human immunodeficiency virus type 1 is initiated at the membrane of infected cells before the release of viral proteins and is required for release to occur with maximum efficiency. J Virol 1994; 68: 6782–6786.
- Katoh E, Louis JM, Yamazaki T, Gronenborn AM, Torchia DA, Ishima R. A solution NMR study of the binding kinetics and the internal dynamics of an HIV-1 protease-substrate complex. Protein Sci 2003; 12: 1376–1385.
- Kellam P, Larder BA. Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates. Antimicrob Agents Chemother 1994; 38: 23–30.
- Kempf DJ, Codacovi L, Wang XC, Kohlbrenner WE, Wideburg NE, Saldivar A, Vasavanonda S, Marsh KC, Bryant P, Sham HL, et al. Symmetry-based inhibitors of HIV protease. Structure-activity studies of acylated 2,4-diamino-1,5-diphenyl-3-hydroxypentane and 2,5-diamino-1,6-diphenylhexane-3,4-diol. J Med Chem 1993; 36: 320–330.
- Kempf DJ, Marsh KC, Denissen JF, McDonald E, Vasavanonda S, Flentge CA, Green BE, Fino L, Park CH, Kong XP, et al. ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. Proc Natl Acad Sci USA 1995; 92: 2484–2488.
- Kempf DJ, Marsh KC, Kumar G, Rodrigues AD, Denissen JF, McDonald E, Kukulka MJ, Hsu A, Granneman GR, Baroldi PA, Sun E, Pizzuti D, Plattner JJ, Norbeck DW, Leonard JM. Pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by coadministration with ritonavir. Antimicrob Agents Chemother 1997; 41: 654–660.
- Kim EE, Baker CT, Dwyer MD, Murcko MA, Rao BG, Tung RD, Navia MA. Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzyme. J Am Chem Soc 1995; 117: 1181–1182.
- King JR, Acosta EP. Tipranavir: a novel nonpeptidic protease inhibitor of HIV. Clin Pharmacokinet 2006; 45: 665–682.
- King NM, Melnick L, Prabu-Jeyabalan M, Nalivaika EA, Yang SS, Gao Y, Nie X, Zepp C, Heefner DL, Schiffer CA. Lack of synergy for inhibitors targeting a multidrug-resistant HIV-1 protease. Protein Sci 2002; 11: 418–429.
- King NM, Prabu-Jeyabalan M, Nalivaika EA, Schiffer CA. Combating susceptibility to drug resistance: lessons from HIV-1 protease. Chem Biol 2004a; 11: 1333–1338.
- King NM, Prabu-Jeyabalan M, Nalivaika EA, Wigerinck P, de Bethune MP, Schiffer CA. Structural and thermodynamic basis for the binding of TMC114, a next-generation human immunodeficiency virus type 1 protease inhibitor. J Virol 2004b; 78: 12012–12021.
- Klei HE, Kish K, Lin PF, Guo Q, Friborg J, Rose RE, Zhang Y, Goldfarb V, Langley DR, Wittekind M, Sheriff S. X-ray crystal structures of human immunodeficiency virus type 1 protease mutants complexed with atazanavir. J Virol 2007; 81: 9525–9535.
- Klein LL, Chen H-J, Yeung MC, Flentge CA, Randolph JT, Huang PP, Hutchinson DK, Kempf DJ. Thiazolyl-carbamate derivatives as cytochrome P450 oxidase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of viral infection. WO 2008027932, 2008.
- Koh Y, Matsumi S, Das D, Amano M, Davis DA, Li J, Leschenko S, Baldridge A, Shioda T, Yarchoan R, Ghosh AK, Mitsuya H. Potent inhibition of HIV-1 replication by novel non-peptidyl small molecule inhibitors of protease dimerization. J Biol Chem 2007; 282: 28709–28720.
- Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM, Sigal IS. Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci USA 1988; 85: 4686–4690.
- Kona J. Theoretical study on the mechanism of a ring-opening reaction of oxirane by the active-site aspartic dyad of HIV-1 protease. Org Biomol Chem 2008; 6: 359–365.
- Kontijevskis A, Wikberg JE, Komorowski J. Computational proteomics analysis of HIV-1 protease interactome. Proteins 2007; 68: 305–312.
- Korant BD, Strack P, Frey MW, Rizzo CJ. A cellular anti-apoptosis protein is cleaved by the HIV-1 protease. Adv Exp Med Biol 1998; 436: 27–29.
- Koudriakova T, Iatsimirskaia E, Utkin I, Gangl E, Vouros P, Storozhuk E, Orza D, Marinina J, Gerber N. Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A by ritonavir. Drug Metab Dispos 1998; 26: 552–561.
- Kovalevsky AY, Liu F, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT. Ultra-high resolution crystal structure of HIV-1 protease mutant reveals two binding sites for clinical inhibitor TMC114. J Mol Biol 2006a; 363: 161–173.
- Kovalevsky AY, Tie Y, Liu F, Boross PI, Wang YF, Leshchenko S, Ghosh AK, Harrison RW, Weber IT. Effectiveness of nonpeptide clinical inhibitor TMC-114 on HIV-1 protease with highly drug resistant mutations D30N, I50V, and L90M. J Med Chem 2006b; 49: 1379–1387.
- Kovalevsky AY, Chumanevich AA, Liu F, Louis JM, Weber IT. Caught in the Act: the 1.5 A resolution crystal structures of the HIV-1 protease and the I54V mutant reveal a tetrahedral reaction intermediate. Biochemistry 2007; 46: 14854–14864.
- Kozisek M, Bray J, Rezacova P, Saskova K, Brynda J, Pokorna J, Mammano F, Rulisek L, Konvalinka J. Molecular analysis of the HIV-1 resistance development: enzymatic activities, crystal structures, and thermodynamics of nelfinavir-resistant HIV protease mutants. J Mol Biol 2007; 374: 1005–1016.
- Krafft GA, Wang GT. Synthetic approaches to continuous assays of retroviral proteases. Methods Enzymol 1994; 241: 70–86.
- Krausslich HG, Facke M, Heuser AM, Konvalinka J, Zentgraf H. The spacer peptide between human immunodeficiency virus capsid and nucleocapsid proteins is essential for ordered assembly and viral infectivity. J Virol 1995; 69: 3407–3419.
- Kumar GN, Rodrigues AD, Buko AM, Denissen JF. Cytochrome P450-mediated metabolism of the HIV-1 protease inhibitor ritonavir (ABT-538) in human liver microsomes. J Pharmacol Exp Ther 1996; 277: 423–431.
- Kumar GN, Dykstra J, Roberts EM, Jayanti VK, Hickman D, Uchic J, Yao Y, Surber B, Thomas S, Granneman GR. Potent inhibition of the cytochrome P-450 3A-mediated human liver microsomal metabolism of a novel HIV protease inhibitor by ritonavir: a positive drug—drug interaction. Drug Metab Dispos 1999; 27: 902–908.
- Kuzmic P. Kinetic assay for HIV proteinase subunit dissociation. Biochem Biophys Res Commun 1993; 191: 998–1003.
- Kuzmic P. Program DYNAFIT for the analysis of enzyme kinetic data: application to HIV proteinase. Anal Biochem 1996; 237: 260–273.
- Lafont V, Armstrong AA, Ohtaka H, Kiso Y, Mario Amzel L, Freire E. Compensating enthalpic and entropic changes hinder binding affinity optimization. Chem Biol Drug Des 2007; 69: 413–422.
- Lam PY, Jadhav PK, Eyermann CJ, Hodge CN, Ru Y, Bacheler LT, Meek JL, Otto MJ, Rayner MM, Wong YN, et al. Rational design of potent, bioavailable, nonpeptide cyclic ureas as HIV protease inhibitors. Science 1994; 263: 380–384.
- Lam PY, Ru Y, Jadhav PK, Aldrich PE, DeLucca GV, Eyermann CJ, Chang CH, Emmett G, Holler ER, Daneker WF, Li L, Confalone PN, McHugh RJ, Han Q, Li R, Markwalder JA, Seitz SP, Sharpe TR, Bacheler LT, Rayner MM, Klabe RM, Shum L, Winslow DL, Kornhauser DM, Hodge CN, et al. Cyclic HIV protease inhibitors: synthesis, conformational analysis, P2/P2′ structure–activity relationship, and molecular recognition of cyclic ureas. J Med Chem 1996; 39: 3514–3525.
- Lamarre D, Croteau G, Wardrop E, Bourgon L, Thibeault D, Clouette C, Vaillancourt M, Cohen E, Pargellis C, Yoakim C, Anderson PC. Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother 1997; 41: 965–971.
- Lapatto R, Blundell T, Hemmings A, Overington J, Wilderspin A, Wood S, Merson JR, Whittle PJ, Danely DE, Geoghegan KF, et al. X-ray analysis of HIV-1 proteinase at 2.7 A resolution confirms structural homology among retroviral enzymes. Nature 1989; 342: 299–302.
- Lenhard JM, Furfine ES, Jain RG, Ittoop O, Orband-Miller LA, Blanchard SG, Paulik MA, Weiel JE. HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res 2000; 47: 121–129.
- Lima VD, Gill VS, Yip B, Hogg RS, Montaner JS, Harrigan PR. Increased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy. J Infect Dis 2008; 198: 51–58.
- Liu F, Boross PI, Wang YF, Tozser J, Louis JM, Harrison RW, Weber IT. Kinetic, stability, and structural changes in high-resolution crystal structures of HIV-1 protease with drug-resistant mutations L24I, I50V, and G73S. J Mol Biol 2005; 354: 789–800.
- Liu F, Kovalevsky AY, Louis JM, Boross PI, Wang YF, Harrison RW, Weber IT. Mechanism of drug resistance revealed by the crystal structure of the unliganded HIV-1 protease with F53L mutation. J Mol Biol 2006; 358: 1191–1199.
- Louis JM, Nashed NT, Parris KD, Kimmel AR, Jerina DM. Kinetics and mechanism of autoprocessing of human immunodeficiency virus type 1 protease from an analog of the Gag-Pol polyprotein. Proc Natl Acad Sci USA 1994; 91: 7970–7974.
- Louis JM, Clore GM, Gronenborn AM. Autoprocessing of HIV-1 protease is tightly coupled to protein folding. Nat Struct Biol 1999a; 6: 868–875.
- Louis JM, Wondrak EM, Kimmel AR, Wingfield PT, Nashed NT. Proteolytic processing of HIV-1 protease precursor, kinetics and mechanism. J Biol Chem 1999b; 274: 23437–23442.
- Louis JM, Ishima R, Torchia DA, Weber IT. HIV-1 protease: structure, dynamics, and inhibition. Adv Pharmacol 2007; 55: 261–298.
- Luque I, Todd MJ, Gomez J, Semo N, Freire E. Molecular basis of resistance to HIV-1 protease inhibition: a plausible hypothesis. Biochemistry 1998; 37: 5791–5797.
- Maguire MF, Guinea R, Griffin P, Macmanus S, Elston RC, Wolfram J, Richards N, Hanlon MH, Porter DJ, Wrin T, Parkin N, Tisdale M, Furfine E, Petropoulos C, Snowden BW, Kleim JP. Changes in human immunodeficiency virus type 1 Gag at positions L449 and P453 are linked to I50V protease mutants in vivo and cause reduction of sensitivity to amprenavir and improved viral fitness in vitro. J Virol 2002; 76: 7398–7406.
- Mahalingam B, Wang YF, Boross PI, Tozser J, Louis JM, Harrison RW, Weber IT. Crystal structures of HIV protease V82A and L90M mutants reveal changes in the indinavir-binding site. Eur J Biochem 2004; 271: 1516–1524.
- Mallon PW. Pathogenesis of lipodystrophy and lipid abnormalities in patients taking antiretroviral therapy. AIDS Rev 2007; 9: 3–15.
- Mammano F, Trouplin V, Zennou V, Clavel F. Retracing the evolutionary pathways of human immunodeficiency virus type 1 resistance to protease inhibitors: virus fitness in the absence and in the presence of drug. J Virol 2000; 74: 8524–8531.
- Martinez-Cajas JL, Wainberg MA. Protease inhibitor resistance in HIV-infected patients: molecular and clinical perspectives. Antiviral Res 2007; 76: 203–221.
- Mascolini M. Ritonavir plus saquinavir: two trials with different results. AIDS Treat News 1996; 5–6.
- Matayoshi ED, Wang GT, Krafft GA, Erickson J. Novel flurogenic substrates for assaying retroviral proteases by resonance energy transfer. Science 1990; 247: 954–958.
- McQuade TJ, Tomasselli AG, Liu L, Karacostas V, Moss B, Sawyer TK, Heinrikson RL, Tarpley WG. A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation. Science 1990; 247: 454–456.
- McTernan CL, McTernan PG, Harte AL, Levick PL, Barnett AH, Kumar S. Resistin, central obesity, and type 2 diabetes. Lancet 2002; 359: 46–47.
- Meek TD, Rodriguez EJ, Angeles TS. Use of steady state kinetic methods to elucidate the kinetic and chemical mechanisms of retroviral proteases. Methods Enzymol 1994; 241: 127–156.
- Mervis RJ, Ahmad N, Lillehoj EP, Raum MG, Salazar FH, Chan HW, Venkatesan S. The gag gene products of human immunodeficiency virus type 1: alignment within the gag open reading frame, identification of posttranslational modifications, and evidence for alternative gag precursors. J Virol 1988; 62: 3993–4002.
- Mildner AM, Rothrock DJ, Leone JW, Bannow CA, Lull JM, Reardon IM, Sarcich JL, Howe WJ, Tomich CS, Smith CW, et al. The HIV-1 protease as enzyme and substrate: mutagenesis of autolysis sites and generation of a stable mutant with retained kinetic properties. Biochemistry 1994; 33: 9405–9413.
- Miller JF, Andrews CW, Brieger M, Furfine ES, Hale MR, Hanlon MH, Hazen RJ, Kaldor I, McLean EW, Reynolds D, Sammond DM, Spaltenstein A, Tung R, Turner EM, Xu RX, Sherrill RG. Ultra-potent P1 modified arylsulfonamide HIV protease inhibitors: the discovery of GW0385. Bioorg Med Chem Lett 2006; 16: 1788–1794.
- Miserez AR, Muller PY, Spaniol V. Indinavir inhibits sterol-regulatory element-binding protein-1c-dependent lipoprotein lipase and fatty acid synthase gene activations. AIDS 2002; 16: 1587–1594.
- Mitsuya H, Maeda K, Das D, Ghosh AK. Development of protease inhibitors and the fight with drug-resistant HIV-1 variants. Adv Pharmacol 2008; 56: 169–197.
- Motwani B, Khayr W. Pharmacoenhancement of protease inhibitors. Am J Ther 2006; 13: 57–63.
- Moyle G. Use of HIV protease inhibitors as pharmacoenhancers. AIDS Read 2001; 11: 87–98.
- Moyle GJ, Back D. Principles and practice of HIV-protease inhibitor pharmacoenhancement. HIV Med 2001; 2: 105–113.
- Murata H, Hruz PW, Mueckler M. Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 2002; 16: 859–863.
- Muzammil S, Ross P, Freire E. A major role for a set of non-active site mutations in the development of HIV-1 protease drug resistance. Biochemistry 2003; 42: 631–638.
- Muzammil S, Armstrong AA, Kang LW, Jakalian A, Bonneau PR, Schmelmer V, Amzel LM, Freire E. Unique thermodynamic response of tipranavir to human immunodeficiency virus type 1 protease drug resistance mutations. J Virol 2007; 81: 5144–5154.
- Myint L, Matsuda M, Matsuda Z, Yokomaku Y, Chiba T, Okano A, Yamada K, Sugiura W. Gag non-cleavage site mutations contribute to full recovery of viral fitness in protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother 2004; 48: 444–452.
- Nalam MN, Peeters A, Jonckers TH, Dierynck I, Schiffer CA. Crystal structure of lysine sulfonamide inhibitor reveals the displacement of the conserved flap water molecule in human immunodeficiency virus type 1 protease. J Virol 2007; 81: 9512–9518.
- Nalam MNL, Schiffer CA. New Approaches to HIV protease inhibitor drug design II: testing the substrate envelope hypothesis to avoid drug resistance and discover robust inhibitors. Curr Opin HIV AIDS 2008; 3: 642–646.
- Navia MA, Fitzgerald PM, McKeever BM, Leu CT, Heimbach JC, Herber WK, Sigal IS, Darke PL, Springer JP. Three-dimensional structure of aspartyl protease from human immunodeficiency virus HIV-1. Nature 1989; 337: 615–620.
- Nguyen AT, Gagnon A, Angel JB, Sorisky A. Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis. AIDS 2000; 14: 2467–2473.
- Nijhuis M, Schuurman R, de Jong D, Erickson J, Gustchina E, Albert J, Schipper P, Gulnik S, Boucher CA. Increased fitness of drug resistant HIV-1 protease as a result of acquisition of compensatory mutations during suboptimal therapy. AIDS 1999; 13: 2349–2359.
- Nijhuis M, van Maarseveen NM, Lastere S, Schipper P, Coakley E, Glass B, Rovenska M, de Jong D, Chappey C, Goedegebuure IW, Heilek-Snyder G, Dulude D, Cammack N, Brakier-Gingras L, Konvalinka J, Parkin N, Krausslich HG, Brun-Vezinet F, Boucher CA. A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med 2007; 4: e36.
- Nillroth U, Vrang L, Markgren PO, Hulten J, Hallberg A, Danielson UH. Human immunodeficiency virus type 1 proteinase resistance to symmetric cyclic urea inhibitor analogs. Antimicrob Agents Chemother 1997; 41: 2383–2388.
- Nivesanond K, Peeters A, Lamoen D, Van Alsenoy C. Conformational analysis of TMC114, a novel HIV-1 protease inhibitor. J Chem Inf Model 2008; 48: 99–108.
- Noor MA. The role of protease inhibitors in the pathogenesis of HIV-associated insulin resistance: cellular mechanisms and clinical implications. Curr HIV/AIDS Rep 2007; 4: 126–134.
- Northrop DB. Follow the protons: a low-barrier hydrogen bond unifies the mechanisms of the aspartic proteases. Acc Chem Res 2001; 34: 790–797.
- Ohtaka H, Muzammil S, Schon A, Velazquez-Campoy A, Vega S, Freire E. Thermodynamic rules for the design of high affinity HIV-1 protease inhibitors with adaptability to mutations and high selectivity towards unwanted targets. Int J Biochem Cell Biol 2004; 36: 1787–1799.
- Ohtaka H, Freire E. Adaptive inhibitors of the HIV-1 protease. Prog Biophys Mol Biol 2005; 88: 193–208.
- Olsen DB, Stahlhut MW, Rutkowski CA, Schock HB, vanOlden AL, Kuo LC. Non-active site changes elicit broad-based cross-resistance of the HIV-1 protease to inhibitors. J Biol Chem 1999; 274: 23699–23701.
- Olson DP, Scadden DT, D' Aquila RT, De Pasquale MP. The protease inhibitor ritonavir inhibits the functional activity of the multidrug resistance related-protein 1 (MRP-1). AIDS 2002; 16: 1743–1747.
- Orans J, Teotico DG, Redinbo MR. The nuclear xenobiotic receptor pregnane X receptor: recent insights and new challenges. Mol Endocrinol 2005; 19: 2891–2900.
- Osborne TF. Sterol regulatory element-binding proteins (SREBPs): key regulators of nutritional homeostasis and insulin action. J Biol Chem 2000; 275: 32379–32382.
- Palmer S, Shafer RW, Merigan TC. Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development. AIDS 1999; 13: 661–667.
- Park C, Choi H, Son Y-C, Lee CS, Choy N, Koh JS, Lee TG, Kwon YD, Kim SC, Yoon H. beta-Methanesulfonyl-L-valine as a novel, unnatural amino acid surrogate for P2 in the design of HIV Protease inhibitors. Bioorg Med Chem Lett 1996; 6: 585.
- Partaledis JA, Yamaguchi K, Tisdale M, Blair EE, Falcione C, Maschera B, Myers RE, Pazhanisamy S, Futer O, Cullinan AB, et al. In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease. J Virol 1995; 69: 5228–5235.
- Paterson DL, Swindells S, Mohr J, Brester M, Vergis EN, Squier C, Wagener MM, Singh N. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133: 21–30.
- Pauwels R, De Clercq E, Desmyter J, Balzarini J, Goubau P, Herdewijn P, Vanderhaeghe H, Vandeputte M. Sensitive and rapid assay on MT-4 cells for detection of antiviral compounds against the AIDS virus. J Virol Methods 1987; 16: 171–185.
- Peranteau AG, Kuzmic P, Angell Y, Garcia-Echeverria C, Rich DH. Increase in fluorescence upon the hydrolysis of tyrosine peptides: application to proteinase assays. Anal Biochem 1995; 227: 242–245.
- Perloff MD, von Moltke LL, Fahey JM, Daily JP, Greenblatt DJ. Induction of P-glycoprotein expression by HIV protease inhibitors in cell culture. AIDS 2000; 14: 1287–1289.
- Perrin V, Mammano F. Parameters driving the selection of nelfinavir-resistant human immunodeficiency virus type 1 variants. J Virol 2003; 77: 10172–10175.
- Petropoulos CJ, Parkin NT, Limoli KL, Lie YS, Wrin T, Huang W, Tian H, Smith D, Winslow GA, Capon DJ, Whitcomb JM. A novel phenotypic drug susceptibility assay for human immunodeficiency virus type 1. Antimicrob Agents Chemother 2000; 44: 920–928.
- Pettit SC, Moody MD, Wehbie RS, Kaplan AH, Nantermet PV, Klein CA, Swanstrom R. The p2 domain of human immunodeficiency virus type 1 Gag regulates sequential proteolytic processing and is required to produce fully infectious virions. J Virol 1994; 68: 8017–8027.
- Pettit SC, Everitt LE, Choudhury S, Dunn BM, Kaplan AH. Initial cleavage of the human immunodeficiency virus type 1 GagPol precursor by its activated protease occurs by an intramolecular mechanism. J Virol 2004; 78: 8477–8485.
- Pettit SC, Lindquist JN, Kaplan AH, Swanstrom R. Processing sites in the human immunodeficiency virus type 1 (HIV-1) Gag-Pro-Pol precursor are cleaved by the viral protease at different rates. Retrovirology 2005; 2: 66.
- Planken SP, Sutton SC, Chen R. Preparation of pyrazole derivatives as cytochrome P450 inhibitors. WO 2008004096, 2008a.
- Planken SP, Sutton SC, Tran TH. Preparation of substituted benzylpyrazoles for inhibiting CYP450 enzyme system. WO 2008004100, 2008b.
- Polgar L, Szeltner Z, Boros I. Substrate-dependent mechanisms in the catalysis of human immunodeficiency virus protease. Biochemistry 1994; 33: 9351–9357.
- Porter DJ, Hanlon MH, Carter LH 3rd, Danger DP, Furfine ES. Effectors of HIV-1 protease peptidolytic activity. Biochemistry 2001; 40: 11131–11139.
- Prabu-Jeyabalan M, Nalivaika E, Schiffer CA. Substrate shape determines specificity of recognition for HIV-1 protease: analysis of crystal structures of six substrate complexes. Structure 2002; 10: 369–381.
- Prabu-Jeyabalan M, Nalivaika EA, King NM, Schiffer CA. Viability of a drug-resistant human immunodeficiency virus type 1 protease variant: structural insights for better antiviral therapy. J Virol 2003; 77: 1306–1315.
- Prabu-Jeyabalan M, King NM, Nalivaika EA, Heilek-Snyder G, Cammack N, Schiffer CA. Substrate envelope and drug resistance: crystal structure of RO1 in complex with wild-type human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother 2006; 50: 1518–1521.
- Prasad JV, Para KS, Tummino PJ, Ferguson D, McQuade TJ, Lunney EA, Rapundalo ST, Batley BL, Hingorani G, Domagala JM, et al. Nonpeptidic potent HIV-1 protease inhibitors: (4-hydroxy-6-phenyl-2-oxo-2H- pyran-3-yl)thiomethanes that span P1-P2′ subsites in a unique mode of active site binding. J Med Chem 1995a; 38: 898–905.
- Prasad JVNV, Lunney EA, Ferguson D, Tummino PJ, Rubin JR, Reyner EL, Stewart BH, Guttendorf RJ, Domagala JM, et al. HIV protease inhibitors possessing a novel, high-affinity, and achiral P1′ /P2′ ligand with a unique pattern of in vitro resistance. Importance of a conformationally-restricted template in the design of enzyme inhibitors. J Am Chem Soc 1995b; 117: 11070–11074.
- Prot M, Heripret L, Cardot-Leccia N, Perrin C, Aouadi M, Lavrut T, Garraffo R, Dellamonica P, Durant J, Le Marchand-Brustel Y, Binetruy B. Long-term treatment with lopinavir—ritonavir induces a reduction in peripheral adipose depots in mice. Antimicrob Agents Chemother 2006; 50: 3998–4004.
- Qari SH, Respess R, Weinstock H, Beltrami EM, Hertogs K, Larder BA, Petropoulos CJ, Hellmann N, Heneine W. Comparative analysis of two commercial phenotypic assays for drug susceptibility testing of human immunodeficiency virus type 1. J Clin Microbiol 2002; 40: 31–35.
- Rajala MW, Qi Y, Patel HR, Takahashi N, Banerjee R, Pajvani UB, Sinha MK, Gingerich RL, Scherer PE, Ahima RS. Regulation of resistin expression and circulating levels in obesity, diabetes, and fasting. Diabetes 2004; 53: 1671–1679.
- Reddy GS, Ali A, Nalam MN, Anjum SG, Cao H, Nathans RS, Schiffer CA, Rana TM. Design and synthesis of HIV-1 protease inhibitors incorporating oxazolidinones as P2/P2′ ligands in pseudosymmetric dipeptide isosteres. J Med Chem 2007a; 50: 4316–4328.
- Reddy YS, Ford SL, Anderson MT, Murray SC, Ng-Cashin J, Johnson MA. Safety and pharmacokinetics of brecanavir, a novel human immunodeficiency virus type 1 protease inhibitor, following repeat administration with and without ritonavir in healthy adult subjects. Antimicrob Agents Chemother 2007b; 51: 1202–1208.
- Reyataz, prescribing information. In: Physicians' Desk Reference, 62nd ed. Montvale, NJ: Thomson Healthcare Inc., 2008, pp. 910–920.
- Riddle TM, Kuhel DG, Woollett LA, Fichtenbaum CJ, Hui DY. HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem 2001; 276: 37514–37519.
- Roberts NA, Martin JA, Kinchington D, Broadhurst AV, Craig JC, Duncan IB, Galpin SA, Handa BK, Kay J, Krohn A, et al. Rational design of peptide-based HIV proteinase inhibitors. Science 1990; 248: 358–361.
- Robinson LH, Myers RE, Snowden BW, Tisdale M, Blair ED. HIV type 1 protease cleavage site mutations and viral fitness: implications for drug susceptibility phenotyping assays. AIDS Res Hum Retroviruses 2000; 16: 1149–1156.
- Rose RE, Gong YF, Greytok JA, Bechtold CM, Terry BJ, Robinson BS, Alam M, Colonno RJ, Lin PF. Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors. Proc Natl Acad Sci USA 1996; 93: 1648–1653.
- Rose RB, Craik CS, Stroud RM. Domain flexibility in retroviral proteases: structural implications for drug resistant mutations. Biochemistry 1998; 37: 2607–2621.
- Schutt M, Meier M, Meyer M, Klein J, Aries SP, Klein HH. The HIV-1 protease inhibitor indinavir impairs insulin signalling in HepG2 hepatoma cells. Diabetologia 2000; 43: 1145–1148.
- Scott JD. Simplifying the treatment of HIV infection with ritonavir-boosted protease inhibitors in antiretroviral-experienced patients. Am J Health Syst Pharm 2005; 62: 809–815.
- Seelmeier S, Schmidt H, Turk V, von der Helm K. Human immunodeficiency virus has an aspartic-type protease that can be inhibited by pepstatin A. Proc Natl Acad Sci USA 1988; 85: 6612–6616.
- Sekar VJ, Lefebvre E, De Pauw M, Vangeneugden T, Hoetelmans RM. Pharmacokinetics of darunavir/ritonavir and ketoconazole following co-administration in HIV-healthy volunteers. Br J Clin Pharmacol 2008; 66: 215–221.
- Sevigny G, Stranix B, Tian B, Dubois A, Sauve G, Petropoulos C, Lie Y, Hellmann N, Conway B, Yelle J. Antiviral activity and cross-resistance profile of P-1946, a novel human immunodeficiency virus type 1 protease inhibitor. Antiviral Res 2006; 70: 17–20.
- Shafer RW, Schapiro JM. HIV-1 drug resistance mutations: an updated framework for the second decade of HAART. AIDS Rev 2008; 10: 67–84.
- Shafer RW, Winters MA, Palmer S, Merigan TC. Multiple concurrent reverse transcriptase and protease mutations and multidrug resistance of HIV-1 isolates from heavily treated patients. Ann Intern Med 1998; 128: 906–911.
- Sham HL, Zhao C, Stewart KD, Betebenner DA, Lin S, Park CH, Kong XP, Rosenbrook W Jr, Herrin T, Madigan D, Vasavanonda S, Lyons N, Molla A, Saldivar A, Marsh KC, McDonald E, Wideburg NE, Denissen JF, Robins T, Kempf DJ, Plattner JJ, Norbeck DW. A novel, picomolar inhibitor of human immuno-deficiency virus type 1 protease. J Med Chem 1996; 39: 392–397.
- Sham HL, Kempf DJ, Molla A, Marsh KC, Kumar GN, Chen CM, Kati W, Stewart K, Lal R, Hsu A, Betebenner D, Korneyeva M, Vasavanonda S, McDonald E, Saldivar A, Wideburg N, Chen X, Niu P, Park C, Jayanti V, Grabowski B, Granneman GR, Sun E, Japour AJ, Leonard JM, Plattner JJ, Norbeck DW. ABT-378, a highly potent inhibitor of the human immunodeficiency virus protease. Antimicrob Agents Chemother 1998; 42: 3218–3224.
- Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ. Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Eur J Endocrinol 2003; 149: 331–335.
- Silva AM, Cachau RE, Sham HL, Erickson JW. Inhibition and catalytic mechanism of HIV-1 aspartic protease. J Mol Biol 1996; 255: 321–346.
- Skulnick HI, Johnson PD, Howe WJ, Tomich PK, Chong KT, Watenpaugh KD, Janakiraman MN, Dolak LA, McGrath JP, Lynn JC, et al. Structure-based design of sulfonamide-substituted non-peptidic HIV protease inhibitors. J Med Chem 1995; 38: 4968–4971.
- Smith AB, 3rd, Hirschmann R, Pasternak A, Yao W, Sprengeler PA, Holloway MK, Kuo LC, Chen Z, Darke PL, Schleif WA. An orally bioavailable pyrrolinone inhibitor of HIV-1 protease: computational analysis and X-ray crystal structure of the enzyme complex. J Med Chem 1997; 40: 2440–2444.
- Snasel J, Pichova I. The cleavage of host cell proteins by HIV-1 protease. Folia Biol (Praha) 1996; 42: 227–230.
- Spaltenstein A, Kazmierski WM, Miller JF, Samano V. Discovery of next generation inhibitors of HIV protease. Curr Top Med Chem 2005; 5: 1589–1607.
- Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA. The hormone resistin links obesity to diabetes. Nature 2001; 409: 307–312.
- Stoll V, Qin W, Stewart KD, Jakob C, Park C, Walter K, Simmer RL, Helfrich R, Bussiere D, Kao J, Kempf D, Sham HL, Norbeck DW. X-ray crystallographic structure of ABT-378 (lopinavir) bound to HIV-1 protease. Bioorg Med Chem 2002; 10: 2803–2806.
- Storch CH, Theile D, Lindenmaier H, Haefeli WE, Weiss J. Comparison of the inhibitory activity of anti-HIV drugs on P-glycoprotein. Biochem Pharmacol 2007; 73: 1573–1581.
- Stranix BR, Sauve G, Bouzide A, Cote A, Sevigny G, Yelle J. Lysine sulfonamides as novel HIV-protease inhibitors: optimization of the N-epsilon-acyl-phenyl spacer. Bioorg Med Chem Lett 2003; 13: 4289–4292.
- Stranix BR, Sauve G, Bouzide A, Cote A, Sevigny G, Yelle J, Perron V. Lysine sulfonamides as novel HIV-protease inhibitors: N-epsilon-disubstituted ureas. Bioorg Med Chem Lett 2004; 14: 3971–3974.
- Stranix BR, Lavallee JF, Sevigny G, Yelle J, Perron V, LeBerre N, Herbart D, Wu JJ. Lysine sulfonamides as novel HIV-protease inhibitors: N-epsilon-acyl aromatic alpha-amino acids. Bioorg Med Chem Lett 2006; 16: 3459–3462.
- Surleraux DLNG, Vendeville SMH, Verschueren WG, De Bethune M-PTMMG, De Kock HA, Tahri A, Erra Sola M. Preparation of 2-(substituted-amino)benzoxazole sulfonamides as broadspectrum HIV protease inhibitors. WO 2002081478, 2002a.
- Surleraux DLNG, Wigerinck PTBP, Getman D, Verschueren WG, Vendeville S, De Bethune M-P, De Kerpel JOA, Moors SLC, De Kock HA, Voets MCJ. Broad-spectrum 2-(substituted-amino)-benzothiazolesulfonamide HIV protease inhibitors. WO 2002083657, 2002b.
- Surleraux DLNG, Vergouwen BJB, De Kock HA. Broad-spectrum substituted benzisoxazole sulfonamide HIV protease inhibitors, preparation thereof, pharmaceutical compositions, diagnostic kits, and combinations with other antiretroviral agents. WO 2003097616, 2003a.
- Surleraux DLNG, Wigerinck PTBP, Voets MCJ, Vendeville SMH, De Kock HA, Vergouwen BJB. Preparation of broad spectrum substituted benzimidazolesulfonamide HIV protease inhibitors. WO 2003076413, 2003b.
- Surleraux DL, de Kock HA, Verschueren WG, Pille GM, Maes LJ, Peeters A, Vendeville S, De Meyer S, Azijn H, Pauwels R, de Bethune MP, King NM, Prabu-Jeyabalan M, Schiffer CA, Wigerinck PB. Design of HIV-1 protease inhibitors active on multidrug-resistant virus. J Med Chem 2005a; 48: 1965–1973.
- Surleraux DL, Tahri A, Verschueren WG, Pille GM, de Kock HA, Jonckers TH, Peeters A, De Meyer S, Azijn H, Pauwels R, de Bethune MP, King NM, Prabu-Jeyabalan M, Schiffer CA, Wigerinck PB. Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor. J Med Chem 2005b; 48: 1813–1822.
- Tahri A, Wigerinck PTBP. Broad spectrum substituted oxindole sulfonamide HIV protease inhibitors. WO 2004016619, 2004.
- Tang J, Hartsuck JA. A kinetic model for comparing proteolytic processing activity and inhibitor resistance potential of mutant HIV-1 proteases. FEBS Lett 1995; 367: 112–116.
- Thaisrivongs S, Tomich PK, Watenpaugh KD, Chong KT, Howe WJ, Yang CP, Strohbach JW, Turner SR, McGrath JP, Bohanon MJ, et al. Structure-based design of HIV protease inhibitors: 4-hydroxycoumarins and 4-hydroxy-2-pyrones as non-peptidic inhibitors. J Med Chem 1994; 37: 3200–3204.
- Thaisrivongs S, Watenpaugh KD, Howe WJ, Tomich PK, Dolak LA, Chong KT, Tomich CC, Tomasselli AG, Turner SR, Strohbach JW, et al. Structure-based design of novel HIV protease inhibitors: carboxamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent nonpeptidic inhibitors. J Med Chem 1995; 38: 3624–3637.
- Thaisrivongs S, Janakiraman MN, Chong KT, Tomich PK, Dolak LA, Turner SR, Strohbach JW, Lynn JC, Horng MM, Hinshaw RR, Watenpaugh KD. Structure-based design of novel HIV protease inhibitors: sulfonamide-containing 4-hydroxycoumarins and 4-hydroxy-2-pyrones as potent non-peptidic inhibitors. J Med Chem 1996; 39: 2400–2410.
- Tie Y, Boross PI, Wang YF, Gaddis L, Hussain AK, Leshchenko S, Ghosh AK, Louis JM, Harrison RW, Weber IT. High resolution crystal structures of HIV-1 protease with a potent non-peptide inhibitor (UIC-94017) active against multi-drug-resistant clinical strains. J Mol Biol 2004; 338: 341–352.
- Tie Y, Boross PI, Wang YF, Gaddis L, Liu F, Chen X, Tozser J, Harrison RW, Weber IT. Molecular basis for substrate recognition and drug resistance from 1.1 to 1.6 angstroms resolution crystal structures of HIV-1 protease mutants with substrate analogs. FEBS J 2005; 272: 5265–5277.
- Tisdale M, Myers RE, Maschera B, Parry NR, Oliver NM, Blair ED. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antimicrob Agents Chemother 1995; 39: 1704–1710.
- Todd MJ, Semo N, Freire E. The structural stability of the HIV-1 protease. J Mol Biol 1998; 283: 475–488.
- Tomasselli AG, Heinrikson RL. Specificity of retroviral proteases: an analysis of viral and nonviral protein substrates. Methods Enzymol 1994; 241: 279–301.
- Tummino PJ, Ferguson D, Hupe D. Competitive inhibition of HIV-1 protease by warfarin derivatives. Biochem Biophys Res Commun 1994; 201: 290–294.
- Tummino PJ, Copeland RA. Residence time of receptor–ligand complexes and its effect on biological function. Biochemistry 2008; 47: 5481–5492.
- Turner SR, Strohbach JW, Tommasi RA, Aristoff PA, Johnson PD, Skulnick HI, Dolak LA, Seest EP, Tomich PK, Bohanon MJ, Horng MM, Lynn JC, Chong KT, Hinshaw RR, Watenpaugh KD, Janakiraman MN, Thaisrivongs S. Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. J Med Chem 1998; 41: 3467–3476.
- Tyndall JD, Pattenden LK, Reid RC, Hu SH, Alewood D, Alewood PF, Walsh T, Fairlie DP, Martin JL. Crystal structures of highly constrained substrate and hydrolysis products bound to HIV-1 protease. Implications for the catalytic mechanism. Biochemistry 2008; 47: 3736–3744.
- Vacca JP, Dorsey BD, Schleif WA, Levin RB, McDaniel SL, Darke PL, Zugay J, Quintero JC, Blahy OM, Roth E, et al. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Proc Natl Acad Sci USA 1994; 91: 4096–4100.
- Vacca JP, Condra JH. Clinically effective HIV-1 protease inhibitors. Drug Discovery Today 1997; 2: 261–272.
- Van't Klooster GAE, Wigerinck PTBP, De Meyer S, Baert LEC, De Kock HA. Use of a sulfonamide compound for improving the pharmacokinetics of a drug. WO 2006108879, 2006.
- Vara Prasad JVN, Para KS, Lunney EA, Ortwine DF, Dunbar JB Jr, Ferguson D, Tummino PJ, Hupe D, Tait BD, et al. Novel series of achiral, low molecular weight, and potent HIV-1 protease inhibitors. J Am Chem Soc 1994; 116: 6989–6990.
- Vazquez ML, Bryant ML, Clare M, DeCrescenzo GA, Doherty EM, Freskos JN, Getman DP, Houseman KA, Julien JA, Kocan GP, et al. Inhibitors of HIV-1 protease containing the novel and potent (R)-(hydroxyethyl)sulfonamide isostere. J Med Chem 1995; 38: 581–584.
- Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 2002; 45: 2615–2623.
- Vega S, Kang LW, Velazquez-Campoy A, Kiso Y, Amzel LM, Freire E. A structural and thermodynamic escape mechanism from a drug resistant mutation of the HIV-1 protease. Proteins 2004; 55: 594–602.
- Vermeiren H, Van Craenenbroeck E, Alen P, Bacheler L, Picchio G, Lecocq P. Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling. J Virol Methods 2007; 145: 47–55.
- von Moltke LL, Durol AL, Duan SX, Greenblatt DJ. Potent mechanism-based inhibition of human CYP3A in vitro by amprenavir and ritonavir: comparison with ketoconazole. Eur J Clin Pharmacol 2000; 56: 259–261.
- Vora S, Marcelin AG, Gunthard HF, Flandre P, Hirsch HH, Masquelier B, Zinkernagel A, Peytavin G, Calvez V, Perrin L, Yerly S. Clinical validation of atazanavir/ritonavir genotypic resistance score in protease inhibitor-experienced patients. AIDS 2006; 20: 35–40.
- Vourvahis M, Kashuba AD. Mechanisms of pharmacokinetic and pharmacodynamic drug interactions associated with ritonavir-enhanced tipranavir. Pharmacotherapy 2007; 27: 888–909.
- Walmsley S. Protease inhibitor-based regimens for HIV therapy: safety and efficacy. JAIDS 2007; 45(Suppl 1): S5–S13.
- Weber IT, Kovalevsky AY, Harrison RW. Structures of HIV protease guide inhibitor design to overcome drug resistance. Frontiers in Drug Design and Discovery 2007; 3: 45–62.
- Wiegers K, Rutter G, Kottler H, Tessmer U, Hohenberg H, Krausslich HG. Sequential steps in human immunodeficiency virus particle maturation revealed by alterations of individual Gag polyprotein cleavage sites. J Virol 1998; 72: 2846–2854.
- Williams JW, Morrison JF. The kinetics of reversible right-binding inhibition. Methods Enzymol 1979; 63: 437–467.
- Wlodawer A, Vondrasek J. Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu Rev Biophys Biomol Struct 1998; 27: 249–284.
- Wlodawer A, Miller M, Jaskolski M, Sathyanarayana BK, Baldwin E, Weber IT, Selk LM, Clawson L, Schneider J, Kent SB. Conserved folding in retroviral proteases: crystal structure of a synthetic HIV-1 protease. Science 1989; 245: 616–621.
- Wondrak EM, Nashed NT, Haber MT, Jerina DM, Louis JM. A transient precursor of the HIV-1 protease. Isolation, characterization, and kinetics of maturation. J Biol Chem 1996; 271: 4477–4481.
- Wood E, Hogg RS, Yip B, Moore D, Harrigan PR, Montaner JS. Superior virological response to boosted protease inhibitor-based highly active antiretroviral therapy in an observational treatment programme. HIV Med 2007; 8: 80–85.
- Wu JJ, Dandache S, Stranix BR, Panchal C, Wainberg MA. The HIV-1 Protease Inhibitor PL-100 has a high genetic barrier and selects a novel pattern of mutations. Antivir Ther 2006; 11: S152.
- Wynne B, Holland A, Ruff D, Guttendorf R. A first-in human study evaluation the safety, tolerability, and pharmacokinetics (PK) of SPI-256, a novel HIV protease inhibitor (PI) administered alone and in combination with ritonavir (RTV) in healthy adult subjects. In: ICAAC, Washington, DC, 2008, Abstract 1265.
- Xie D, Gulnik S, Collins L, Gustchina E, Bhat TN, Erickson JW. Thermodynamics and proton uptake for pepstatin binding to retroviral and eukaryotic aspartic proteases. Adv Exp Med Biol 1998; 436: 381–386.
- Xie D, Gulnik S, Gustchina E, Yu B, Shao W, Qoronfleh W, Nathan A, Erickson JW. Drug resistance mutations can effect dimer stability of HIV-1 protease at neutral pH. Protein Sci 1999; 8: 1702–1707.
- Yan Q, Hruz PW. Direct comparison of the acute in vivo effects of HIV protease inhibitors on peripheral glucose disposal. JAIDS 2005; 40: 398–403.
- Yang Y, Ikezoe T, Nishioka C, Bandobashi K, Takeuchi T, Adachi Y, Kobayashi M, Takeuchi S, Koeffler HP, Taguchi H. NFV, an HIV-1 protease inhibitor, induces growth arrest, reduced Akt signalling, apoptosis and docetaxel sensitisation in NSCLC cell lines. Br J Cancer 2006; 95: 1653–1662.
- Yeh RF, Gaver VE, Patterson KB, Rezk NL, Baxter-Meheux F, Blake MJ, Eron JJ Jr, Klein CE, Rublein JC, Kashuba AD. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. JAIDS 2006; 42: 52–60.
- Yoshimura K, Kato R, Kavlick MF, Nguyen A, Maroun V, Maeda K, Hussain KA, Ghosh AK, Gulnik SV, Erickson JW, Mitsuya H. A potent human immunodeficiency virus type 1 protease inhibitor, UIC-94003 (TMC-126), and selection of a novel (A28S) mutation in the protease active site. J Virol 2002; 76: 1349–1358.
- Youle M. Overview of boosted protease inhibitors in treatment-experienced HIV-infected patients. J Antimicrob Chemother 2007; 60: 1195–1205.
- Yusa K, Harada S. Acquisition of multi-PI (protease inhibitor) resistance in HIV-1 in vivo and in vitro. Curr Pharm Des 2004; 10: 4055–4064.
- Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavirboosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother 2004; 53: 4–9.
- Zhang D, Chando TJ, Everett DW, Patten CJ, Dehal SS, Humphreys WG. In vitro inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo bilirubin glucuronidation. Drug Metab Dispos 2005; 33: 1729–1739.
- Zhang YM, Imamichi H, Imamichi T, Lane HC, Falloon J, Vasudevachari MB, Salzman NP. Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol 1997; 71: 6662–6670.
- Zhang ZY, Poorman RA, Maggiora LL, Heinrikson RL, Kezdy FJ. Dissociative inhibition of dimeric enzymes. Kinetic characterization of the inhibition of HIV-1 protease by its COOH-terminal tetrapeptide. J Biol Chem 1991; 266: 15591–15594.
- Zhou H, Pandak WM Jr, Lyall V, Natarajan R, Hylemon PB. HIV protease inhibitors activate the unfolded protein response in macrophages: implication for atherosclerosis and cardiovascular disease. Mol Pharmacol 2005; 68: 690–700.
- Zhou H, Gurley EC, Jarujaron S, Ding H, Fang Y, Xu Z, Pandak WM Jr, Hylemon PB. HIV protease inhibitors activate the unfolded protein response and disrupt lipid metabolism in primary hepatocytes. Am J Physiol Gastrointest Liver Physiol 2006; 291: G1071–G1080.
- Zhou J, Yuan X, Dismuke D, Forshey BM, Lundquist C, Lee KH, Aiken C, Chen CH. Small-molecule inhibition of human immunodeficiency virus type 1 replication by specific targeting of the final step of virion maturation. J Virol 2004; 78: 922–929.
- Ziermann R, Limoli K, Das K, Arnold E, Petropoulos CJ, Parkin NT. A mutation in human immunodeficiency virus type 1 protease, N88S, that causes in vitro hypersensitivity to amprenavir. J Virol 2000; 74: 4414–4419.