Discovery of Inhibitors of Shiga Toxin Type 2 by On-Plate Generation and Screening of a Focused Compound Library†
Dr. Somnath Dasgupta
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Search for more papers by this authorDr. Pavel I. Kitov
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Search for more papers by this authorJoanna M. Sadowska
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Search for more papers by this authorCorresponding Author
Prof. Dr. David R. Bundle
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htmSearch for more papers by this authorDr. Somnath Dasgupta
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Search for more papers by this authorDr. Pavel I. Kitov
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Search for more papers by this authorJoanna M. Sadowska
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Search for more papers by this authorCorresponding Author
Prof. Dr. David R. Bundle
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htm
Alberta Glycomics Centre, Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2 (Canada) http://www.chem.ualberta.ca/∼glyco/who/index.htmSearch for more papers by this authorThis work was supported by a grant from Alberta Innovates, Technology Futures.
Abstract
A new microtiter-plate-based method for the rapid generation and evaluation of focused compound libraries was developed and applied to screening ligand analogues for the E. coli Shiga-like toxin Stx2a. The method is general, it mitigates the masking of intrinsic affinity gains by multivalency and enables the discovery of potential hits when starting from ligands that exhibit extremely low affinity with proteins that depend on multivalency for their function.
Supporting Information
As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re-organized for online delivery, but are not copy-edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.
| Filename | Description |
|---|---|
| ange_201309436_sm_miscellaneous_information.pdf995.8 KB | miscellaneous_information |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- 1
- 1aP. I. Tarr, C. A. Gordon, W. L. Chandler, Lancet 2005, 365, 1073–1086;
- 1bD. A. Rasko, D. R. Webster, J. W. Sahl, A. Bashir, N. Boisen, F. Scheutz, E. E. Paxinos, R. Sebra, C. S. Chin, D. Iliopoulos, A. Klammer, P. Peluso, L. Lee, A. O. Kislyuk, J. Bullard, A. Kasarskis, S. Wang, J. Eid, D. Rank, J. C. Redman, S. R. Steyert, J. Frimodt-Moller, C. Struve, A. M. Petersen, K. A. Krogfelt, J. P. Nataro, E. E. Schadt, M. K. Waldor, N. Engl. J. Med. 2011, 365, 709–717.
- 2
- 2aJ. C. Paton, A. W. Paton, Clin. Microbiol. Rev. 1998, 11, 450–479;
- 2bP. M. Griffin, Escherichia coli O157:H7 and other enterohemorrhagic Escherichia coli, Raven, San Diego, 1995;
- 2cP. M. Griffin, R. V. Tauxe, Epidemiol. Rev. 1991, 13, 60–98.
- 3
- 3aC. S. Wong, S. Jelacic, R. L. Habeeb, S. L. Watkins, P. I. Tarr, N. Engl. J. Med. 2000, 342, 1930–1936;
- 3bC. M. McGannon, C. A. Fuller, A. A. Weiss, Antimicrob. Agents Chemother. 2010, 54, 3790–3798.
- 4
- 4aA. E. Clatworthy, E. Pierson, D. T. Hung, Nat. Chem. Biol. 2007, 3, 541–548;
- 4bL. Cegelski, G. R. Marshall, G. R. Eldridge, S. J. Hultgren, Nat. Rev. Microbiol. 2008, 6, 17–27.
- 5D. A. Rasko, V. Sperandio, Nat. Rev. Drug Discovery 2010, 9, 117–128.
- 6G. Schiavo, F. G. van der Goot, Nat. Rev. Mol. Cell Biol. 2001, 2, 530–537.
- 7L. Johannes, W. Romer, Nat. Rev. Microbiol. 2010, 8, 105–116.
- 8M. A. Karmali, M. Petric, C. Lim, P. C. Fleming, G. S. Arbus, H. Lior, J. Infect. Dis. 1985, 151, 775–782.
- 9
- 9aJ. Lundquist, S. Debenham, E. Toone, J. Org. Chem. 2000, 65, 8245–8250;
- 9bE. N. Kitova, P. I. Kitov, D. R. Bundle, J. S. Klassen, Glycobiology 2001, 11, 605–611.
- 10
- 10aP. I. Kitov, J. M. Sadowska, G. Mulvey, G. D. Armstrong, H. Ling, N. S. Pannu, R. J. Read, D. R. Bundle, Nature 2000, 403, 669–672;
- 10bG. L. Mulvey, P. Marcato, P. I. Kitov, J. Sadowska, D. R. Bundle, G. D. Armstrong, J. Infect. Dis. 2003, 187, 640–649;
- 10cP. I. Kitov, G. L. Mulvey, T. P. Griener, T. Lipinski, D. Solomon, E. Paszkiewicz, J. M. Jacobson, J. M. Sadowska, M. Suzuki, K. Yamamura, G. D. Armstrong, D. R. Bundle, Proc. Natl. Acad. Sci. USA 2008, 105, 16837–16842.
- 11K. Nishikawa, K. Matsuoka, E. Kita, N. Okabe, M. Mizuguchi, K. Hino, S. Miyazawa, C. Yamasaki, J. Aoki, S. Takashima, Y. Yamakawa, M. Nishijima, D. Terunuma, H. Kuzuhara, Y. Natori, Proc. Natl. Acad. Sci. USA 2002, 99, 7669–7674.
- 12N. W. P. Rutjes, B. A. Binnington, C. R. Smith, M. D. Maloney, C. A. Lingwood, Kidney Int. 2002, 62, 832–845.
- 13R. L. Siegler, T. G. Obrig, T. J. Pysher, V. L. Tesh, N. D. Denkers, F. B. Taylor, Pediatr. Nephrol. 2003, 18, 92–96.
- 14
- 14aM. R. Leslie, H. Parolis, L. A. S. Parolis, Carbohydr. Res. 2000, 324-329, 103–110;
- 14bS. D. Gamage, C. M. McGannon, A. A. Weiss, J. Bacteriol. 2004, 186, 5506–5512.
- 15
- 15aR. R. Kale, C. M. McGannon, C. Fuller-Schaefer, D. M. Hatch, M. J. Flagler, S. D. Gamage, A. A. Weiss, S. S. Iyer, Angew. Chem. 2008, 120, 1285–1288;
10.1002/ange.200703680 Google ScholarAngew. Chem. Int. Ed. 2008, 47, 1265–1268; H. O. Yosief, S. S. Iyer, A. A. Weiss, Infect. Immun. 2013, 81, 2753–2760.
- 16J. M. Jacobson, J. Yin, P. I. Kitov, G. Mulvey, T. Griener, M. James, G. Armstrong, D. R. Bundle, J. Biol. Chem. 2013, DOI:.
- 17P. I. Kitov, Y. Kotsuchibashi, E. Paszkiewicz, D. Wilhelm, R. Narain, D. R. Bundle, Org. Lett. 2013, 15, 5190–5193.
- 18Synthetic procedures, spectral data, conditions for plate treatment, and details for binding and inhibiton assays, are presented in the Supporting Information. In the present work, we used the previously described [17] copovidone sample. Briefly, a statistical copolymer (NVP/VA=7.3:1, Mn=36700 Da, PDI=1.69) was obtained by RAFT polymerization of NVP and VA and characterized by size-exclusion chromatography and NMR spectroscopy. The degree of modification in all subsequent derivatives of the original polymer was deduced from the NMR spectra.
- 19The sample of Stx2a was a generous gift from Prof. G. D. Armstrong. Stx2a was isolated and purified as described in G. Mulvey, R. Vanmaele, M. Mrazek, M. Gahill, G. D. Armstrong, J. Microbiol. Methods 1998, 17, 247–252.
- 20H. Ling, A. Boodhoo, B. Hazes, M. D. Cummings, G. D. Armstrong, J. L. Brunton, R. J. Read, Biochemistry 1998, 37, 1777–1788.
- 21
- 21aK. Godula, C. R. Bertozzi, J. Am. Chem. Soc. 2012, 134, 15732–15742;
- 21bC. D. Rillahan, E. Schwartz, C. Rademacher, R. McBride, J. Rangarajan, V. V. Fokin, J. C. Paulson, ACS Chem. Biol. 2013, 8, 1417–1422.
- 22S. L. Mangold, M. J. Cloninger, Org. Biomol. Chem. 2006, 4, 2458–2465.
- 23See, for example, D. Ponader, F. Wojcik, F. Beceren-Braun, J. Dernedde, L. Hartmann, Biomacromolecules 2012, 13, 1845–1852, and references therein.
Citing Literature
This is the
German version
of Angewandte Chemie.
Note for articles published since 1962:
Do not cite this version alone.
Take me to the International Edition version with citable page numbers, DOI, and citation export.
We apologize for the inconvenience.
