A Versatile Strategy for Screening Custom-Designed Warhead-Armed Cyclic Peptide Inhibitors |
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Authors: | Deokhee Kang Do-Wook Kim Joo-Chan Kim Prof. Hee-Sung Park |
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Affiliation: | Department of Chemistry, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, 34141 Korea |
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Abstract: | 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. |
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Keywords: | Cyclic Peptide Inhibitor Genetic Code Expansion Warhead-Bearing Unnatural Amino Acid |
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