Nitrile-Based Inhibitors Targeting both SARS-CoV-2 Main Protease and Human Cathepsin L

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-09-10 Epub Date: 2026-08-29 DOI:10.1021/acsmedchemlett.6c00236

Leonard Barasa, Yongzhi Chen, Ala M. Shaqra, Syeda F. Z. Adnan, Lauren E. Intravaia, Sandeep Huchaiah, Akumalla Allabaji, Karthik Kumar S, Srinivasa Rao Vidadala, Santoshkumar N. Patil, Jeffrey Hale, Celia A. Schiffer, Katherine A. Fitzgerald, Paul R. Thompson

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引用次数: 0

Abstract

The SARS-CoV-2 main protease (M^pro) and host cysteine protease cathepsin L (CatL) are both attractive targets for antiviral intervention. Herein we describe the rational design and synthesis of dual M^pro/CatL inhibitors derived from the previously reported leads SM141 and SM142. Optimization focused on replacement of the acrylate ester warhead in SM141 and SM142 with a nitrile, modifying the P2, P3, and P4 capping groups, and variation of the P1 lactam ring size. In addition, conformational restriction was achieved through macrocyclization between the P1 and P4 side chains to enhance binding affinity. These efforts identified multiple dual-target inhibitors with nanomolar potency against both M^pro and CatL and potent antiviral activity as well as selective M^pro inhibitors with strong enzymatic activity. Targeting both a viral protease and a host factor may provide more durable antiviral efficacy by reducing susceptibility to resistance arising from viral evolution of M^pro.

查看原文本刊更多论文

靶向SARS-CoV-2主蛋白酶和人组织蛋白酶L的腈基抑制剂

SARS-CoV-2主蛋白酶（Mpro）和宿主半胱氨酸蛋白酶组织蛋白酶L （CatL）都是抗病毒干预的有吸引力的靶点。在这里，我们描述了合理的设计和合成的双重Mpro/CatL抑制剂衍生自先前报道的先导物SM141和SM142。优化的重点是将SM141和SM142中的丙烯酸酯战斗部替换为腈战斗部，修改P2、P3和p4封盖基团，以及改变P1内酰胺环的尺寸。此外，通过P1和P4侧链之间的大环化实现构象限制，以增强结合亲和力。这些努力确定了多种双靶点抑制剂，具有纳米摩尔的抗Mpro和CatL的效力，以及有效的抗病毒活性，以及具有强酶活性的选择性Mpro抑制剂。同时靶向病毒蛋白酶和宿主因子可能通过降低对Mpro病毒进化引起的耐药性的易感性而提供更持久的抗病毒功效。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.