低纳摩尔效度酮苯并噻唑类肽类TMPRSS13抑制剂的研制。

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Alexandre Joushomme, Antoine Désilets, William Champagne, Malihe Hassanzadeh, Gabriel Lemieux, Alice Gravel-Trudeau, Matthieu Lepage, Sabrina Lafrenière, Ulrike Froehlich, Karin List, Pierre-Luc Boudreault, Richard Leduc
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引用次数: 0

摘要

TMPRSS13是II型跨膜丝氨酸蛋白酶(TTSP)家族的一员,参与癌症进展和呼吸道病毒细胞进入。到目前为止,还没有专门针对这种蛋白酶开发的抑制剂。在这项研究中,我们筛选了65个酮苯并噻唑类拟肽分子的化学文库,以对抗具有蛋白水解活性的重组TMPRSS13,以鉴定新的抑制剂。在首轮筛选之后,随后在分子模拟的支持下合成了其他衍生物,揭示了参与TMPRSS13抑制的重要分子决定因素。一种抑制剂N-0430在细胞环境中对TMPRSS13活性具有低纳摩尔亲和力。利用SARS-CoV-2假病毒进入细胞模型,我们进一步证明了N-0430能够阻断依赖tmprss13的假病毒进入细胞。已确定的拟肽抑制剂以及从本研究中获得的对其效力的分子见解将有助于开发特异性TMPRSS13抑制剂。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Development of ketobenzothiazole-based peptidomimetic TMPRSS13 inhibitors with low nanomolar potency.

TMPRSS13, a member of the Type II Transmembrane Serine Proteases (TTSP) family, is involved in cancer progression and in respiratory virus cell entry. To date, no inhibitors have been specifically developed for this protease. In this study, a chemical library of 65 ketobenzothiazole-based peptidomimetic molecules was screened against a proteolytically active form of recombinant TMPRSS13 to identify novel inhibitors. Following an initial round of screening, subsequent synthesis of additional derivatives supported by molecular modelling revealed important molecular determinants involved in TMPRSS13 inhibition. One inhibitor, N-0430, achieved low nanomolar affinity towards TMPRSS13 activity in a cellular context. Using a SARS-CoV-2 pseudovirus cell entry model, we further demonstrated the ability of N-0430 to block TMPRSS13-dependent entry of the pseudovirus. The identified peptidomimetic inhibitors and the molecular insights into their potency gained from this study will aid in the development of specific TMPRSS13 inhibitors.

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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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