A Versatile Strategy for Screening Custom-Designed Warhead-Armed Cyclic Peptide Inhibitors
Deokhee Kang
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
These authors contributed equally to this work.
Contribution: Conceptualization (equal), Data curation (equal), Methodology (equal), Validation (equal), Writing - original draft (equal)
Search for more papers by this authorDo-Wook Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
These authors contributed equally to this work.
Contribution: Conceptualization (equal), Data curation (equal), Methodology (equal), Validation (equal), Writing - original draft (supporting)
Search for more papers by this authorJoo-Chan Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
Contribution: Formal analysis (supporting), Methodology (supporting), Visualization (supporting)
Search for more papers by this authorCorresponding Author
Prof. Hee-Sung Park
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Funding acquisition (lead), Investigation (lead), Project administration (lead), Resources (lead), Supervision (lead), Validation (lead), Writing - original draft (lead), Writing - review & editing (lead)
Search for more papers by this authorDeokhee Kang
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
These authors contributed equally to this work.
Contribution: Conceptualization (equal), Data curation (equal), Methodology (equal), Validation (equal), Writing - original draft (equal)
Search for more papers by this authorDo-Wook Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
These authors contributed equally to this work.
Contribution: Conceptualization (equal), Data curation (equal), Methodology (equal), Validation (equal), Writing - original draft (supporting)
Search for more papers by this authorJoo-Chan Kim
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
Contribution: Formal analysis (supporting), Methodology (supporting), Visualization (supporting)
Search for more papers by this authorCorresponding Author
Prof. Hee-Sung Park
Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea
Contribution: Conceptualization (lead), Data curation (lead), Formal analysis (lead), Funding acquisition (lead), Investigation (lead), Project administration (lead), Resources (lead), Supervision (lead), Validation (lead), Writing - original draft (lead), Writing - review & editing (lead)
Search for more papers by this authorAbstract
Demand for peptide-based pharmaceuticals has been steadily increasing, but only limited success has been achieved to date. To expedite peptide-based drug discovery, we developed a general scheme for cell-based screening of cyclic peptide inhibitors armed with a user-designed warhead. We combined unnatural amino acid incorporation and split intein-mediated peptide cyclization techniques and integrated a yeast-based colorimetric screening assay to generate a new scheme that we call the custom-designed warhead-armed cyclic peptide screening platform (CWCPS). This strategy successfully discovered a potent inhibitor, CY5-6Q, that targets human histone deacetylase 8 (HDAC8) with a KD value of 15 nM. This approach can be a versatile and general platform for discovering cyclic peptide inhibitors.
Conflict of interest
The authors declare no conflict of interest.
Open Research
Data Availability Statement
The data that support the findings of this study are available in the Supporting Information of this article.
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 |
|---|---|
| ange202214815-sup-0001-misc_information.pdf2 MB | Supporting 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
- 1aG. P. Smith, Science 1985, 228, 1315–1317;
- 1bJ. M. Tharp, J. Hampton, C. A. Reed, A. Ehnbom, P.-H. C. Chen, J. S. Morse, Y. Kurra, L. M. Pérez, S. Xu, W. R. Liu, Nat. Commun. 2020, 11, 1392;
- 1cX. S. Wang, P. H. C. Chen, J. T. Hampton, J. M. Tharp, C. A. Reed, S. K. Das, D. S. Wang, H. S. Hayatshahi, Y. Shen, J. Liu, Angew. Chem. Int. Ed. 2019, 58, 15904–15909; Angew. Chem. 2019, 131, 16051–16056.
- 2
- 2aD. S. Wilson, A. D. Keefe, J. W. Szostak, Proc. Natl. Acad. Sci. USA 2001, 98, 3750–3755;
- 2bY. Goto, A. Ohta, Y. Sako, Y. Yamagishi, H. Murakami, H. Suga, ACS Chem. Biol. 2008, 3, 120–129;
- 2cY. Huang, M. M. Wiedmann, H. Suga, Chem. Rev. 2019, 119, 10360–10391.
- 3A. Zorzi, K. Deyle, C. Heinis, Curr. Opin. Chem. Biol. 2017, 38, 24–29.
- 4
- 4aJ. R. Frost, Z. Wu, Y. C. Lam, A. E. Owens, R. Fasan, Org. Biomol. Chem. 2016, 14, 5803–5812;
- 4bA. E. Owens, I. De Paola, W. A. Hansen, Y.-W. Liu, S. D. Khare, R. Fasan, J. Am. Chem. Soc. 2017, 139, 12559–12568.
- 5
- 5aK. Barreto, V. Bharathikumar, A. Ricardo, J. F. DeCoteau, Y. Luo, C. R. Geyer, Chem. Biol. 2009, 16, 1148–1157;
- 5bV. Bharathikumar, K. Barreto, J. F. DeCoteau, C. R. Geyer, ChemBioChem 2013, 14, 2119–2125;
- 5cA. Tavassoli, S. J. Benkovic, Angew. Chem. Int. Ed. 2005, 44, 2760–2763; Angew. Chem. 2005, 117, 2820–2823;
- 5dA. Tavassoli, Q. Lu, J. Gam, H. Pan, S. J. Benkovic, S. N. Cohen, ACS Chem. Biol. 2008, 3, 757–764;
- 5eA. Tavassoli, Curr. Opin. Chem. Biol. 2017, 38, 30–35;
- 5fA. R. Horswill, S. J. Benkovic, Cell Cycle 2005, 4, 552–555;
- 5gN. Bionda, R. Fasan, ChemBioChem 2015, 16, 2011–2016.
- 6M. Gehringer, S. A. Laufer, J. Med. Chem. 2019, 62, 5673–5724.
- 7J. Morimoto, Y. Hayashi, H. Suga, Angew. Chem. Int. Ed. 2012, 51, 3423–3427; Angew. Chem. 2012, 124, 3479–3483.
- 8A. Chakrabarti, I. Oehme, O. Witt, G. Oliveira, W. Sippl, C. Romier, R. J. Pierce, M. Jung, Trends Pharmacol. Sci. 2015, 36, 481–492.
- 9F. J. Kaiser, M. Ansari, D. Braunholz, M. Concepción Gil-Rodríguez, C. Decroos, J. J. Wilde, C. T. Fincher, M. Kaur, M. Bando, D. J. Amor, Hum. Mol. Genet. 2014, 23, 2888–2900.
- 10M. A. Deardorff, N. J. Porter, D. W. Christianson, Protein Sci. 2016, 25, 1965–1976.
- 11S. Shen, A. P. Kozikowski, ChemMedChem 2016, 11, 15–21.
- 12R. Benigni, L. Passerini, Mutat. Res. Rev. Mutat. Res. 2002, 511, 191–206.
- 13S. Lechner, M. I. P. Malgapo, C. Grätz, R. R. Steimbach, A. Baron, P. Rüther, S. Nadal, C. Stumpf, C. Loos, X. Ku, Nat. Chem. Biol. 2022, 18, 812–820.
- 14K. N. Allen, R. H. Abeles, Biochemistry 1989, 28, 8466–8473.
- 15D. Mumberg, R. Müller, M. Funk, Gene 1995, 156, 119–122.
- 16A. Deshiere, E. Duchemin-Pelletier, E. Spreux, D. Ciais, F. Combes, Y. Vandenbrouck, Y. Couté, I. Mikaelian, S. Giusiano, C. Charpin, Oncogene 2013, 32, 1373–1383.
- 17
- 17aT. Umehara, J. Kim, S. Lee, L.-T. Guo, D. Söll, H.-S. Park, FEBS Lett. 2012, 586, 729–733;
- 17bD. I. Bryson, C. Fan, L.-T. Guo, C. Miller, D. Söll, D. R. Liu, Nat. Chem. Biol. 2017, 13, 1253–1260;
- 17cS. M. Hancock, R. Uprety, A. Deiters, J. W. Chin, J. Am. Chem. Soc. 2010, 132, 14819–14824.
- 18T. Suzuki, C. Miller, L.-T. Guo, J. M. Ho, D. I. Bryson, Y.-S. Wang, D. R. Liu, D. Söll, Nat. Chem. Biol. 2017, 13, 1261–1266.
- 19A. Chakrabarti, J. Melesina, F. R. Kolbinger, I. Oehme, J. Senger, O. Witt, W. Sippl, M. Jung, Future Med. Chem. 2016, 8, 1609–1634.
- 20
- 20aY. Ding, J. P. Ting, J. Liu, S. Al-Azzam, P. Pandya, S. Afshar, Amino Acids 2020, 52, 1207–1226;
- 20bY. Goto, H. Suga, Acc. Chem. Res. 2021, 54, 3604–3617;
- 20cA. K. Ghosh, I. Samanta, A. Mondal, W. R. Liu, ChemMedChem 2019, 14, 889–906.
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.
