University of Sussex
Browse

File(s) under permanent embargo

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 Wright
A 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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Bioorganic and Medicinal Chemistry Letters

ISSN

0960-894X

Publisher

Elsevier

Issue

19

Volume

20

Page range

5695-5700

Department affiliated with

  • Chemistry Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2015-07-21

First Compliant Deposit (FCD) Date

2015-07-20

Usage metrics

    University of Sussex (Publications)

    Categories

    No categories selected

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC