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Novel macrocyclic HCV NS3 protease inhibitors derived from a-amino cyclic boronates
journal contribution
posted on 2023-06-08, 21:48 authored by Xianfeng Li, Yong-Kang Zhang, Yang Liu, Charles Z Ding, Yasheen Zhou, Qun Li, Jacob J Plattner, Stephen J Baker, Suoming Zhang, Wieslaw M Kazmierski, Lois L Wright, Gary K Smith, Richard M Grimes, Renae M Crosby, Katrina L Creech, Luz H Carballo, Martin J Slater, Richard L Jarvest, Pia Thommes, Julia A Hubbard, Maire A Convery, Pamela M Nassau, William McDowell, Tadeusz J Skarzynski, Xuelei Qian, Dazhong Fan, Liang Liao, Zhi-Jie Ni, Lewis E Pennicott, Wuxin Zou, Jon WrightA novel series of P2-P4 macrocyclic HCV NS3/4A protease inhibitors with a-amino cyclic boronates as warheads at the P1 site was designed and synthesized. When compared to their linear analogs, these macrocyclic inhibitors exhibited a remarkable improvement in cell-based replicon activities, with compounds 9a and 9e reaching sub-micromolar potency in replicon assay. The SAR around a-amino cyclic boronates clearly established the influence of ring size, chirality and of the substitution pattern. Furthermore, X-ray structure of the co-crystal of inhibitor 9a and NS3 protease revealed that Ser-139 in the enzyme active site traps boron in the warhead region of 9a, thus establishing its mode of action.
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Publication status
- Published
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- Published version
Journal
Bioorganic and Medicinal Chemistry LettersISSN
0960-894XPublisher
ElsevierExternal DOI
Issue
19Volume
20Page range
5695-5700Department affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-07-21First Compliant Deposit (FCD) Date
2015-07-20Usage metrics
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