Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors,RSC Medicinal Chemistry

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Peptidomimetic nitrile warheads as SARS-CoV-2 3CL protease inhibitors
RSC Medicinal Chemistry ( IF 4.1 ) Pub Date : 2021-08-20 , DOI: 10.1039/d1md00247c
Bing Bai _{1,

2} , Elena Arutyunova _{3,

4} , Muhammad Bashir Khan ₃ , Jimmy Lu _{2,

4} , Michael A Joyce _{2,

4} , Holly A Saffran _{2,

4} , Justin A Shields _{2,

4} , Appan Srinivas Kandadai _{1,

2} , Alexandr Belovodskiy _{1,

2} , Mostofa Hena _{1,

2} , Wayne Vuong ₅ , Tess Lamer ₅ , Howard S Young ₄ , John C Vederas ₅ , D Lorne Tyrrell _{1,

2,

4} , M Joanne Lemieux _{3,

4} , James A Nieman _{1,

2}

Affiliation

Tragically, the death toll from the COVID-19 pandemic continues to rise, and with variants being observed around the globe new therapeutics, particularly direct-acting antivirals that are easily administered, are desperately needed. Studies targeting the SARS-CoV-2 3CL protease, which is critical for viral replication, with different peptidomimetics and warheads is an active area of research for development of potential drugs. To date, however, only a few publications have evaluated the nitrile warhead as a viral 3CL protease inhibitor, with only modest activity reported. This article describes our investigation of P3 4-methoxyindole peptidomimetic analogs with select P1 and P2 groups with a nitrile warhead that are potent inhibitors of SARS-CoV-2 3CL protease and demonstrate in vitro SARS-CoV-2 antiviral activity. A selectivity for SARS-CoV-2 3CL protease over human cathepsins B, S and L was also observed with the nitrile warhead, which was superior to that with the aldehyde warhead. A co-crystal structure with SARS-CoV-2 3CL protease and a reversibility study indicate that a reversible, thioimidate adduct is formed when the catalytic sulfur forms a covalent bond with the carbon of the nitrile. This effort also identified efflux as a property limiting antiviral activity of these compounds, and together with the positive attributes described these results provide insight for further drug development of novel nitrile peptidomimetics targeting SARS-CoV-2 3CL protease.

中文翻译：

作为 SARS-CoV-2 3CL 蛋白酶抑制剂的拟肽腈弹头

悲惨的是，新冠肺炎 (COVID-19) 大流行造成的死亡人数持续上升，而且随着全球范围内观察到病毒变异，迫切需要新的治疗方法，特别是易于施用的直接作用抗病毒药物。针对 SARS-CoV-2 3CL 蛋白酶（对病毒复制至关重要）的研究以及不同的肽模拟物和弹头是潜在药物开发研究的活跃领域。然而，迄今为止，只有少数出版物评估了腈弹头作为病毒 3CL 蛋白酶抑制剂的作用，并且只报道了适度的活性。本文介绍了我们对 P3 4-甲氧基吲哚拟肽类似物的研究，其中包含带有腈弹头的选定 P1 和 P2 基团，它们是 SARS-CoV-2 3CL 蛋白酶的有效抑制剂，并证明了体外SARS -CoV-2 抗病毒活性。还观察到腈弹头对 SARS-CoV-2 3CL 蛋白酶相对于人组织蛋白酶 B、S 和 L 的选择性，优于醛弹头。与 SARS-CoV-2 3CL 蛋白酶的共晶结构和可逆性研究表明，当催化硫与腈的碳形成共价键时，会形成可逆的硫代亚氨酸盐加合物。这项工作还确定了外排是限制这些化合物抗病毒活性的一种特性，连同所描述的积极属性，这些结果为进一步开发针对 SARS-CoV-2 3CL 蛋白酶的新型腈肽模拟物提供了见解。

更新日期：2021-09-01

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