Peptide Aldehydes Incorporating Thiazol-4-yl Alanine Are Potent In Vitro Inhibitors of SARS-CoV-2 Main Protease

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-11-03 DOI:10.1021/acsmedchemlett.4c0044410.1021/acsmedchemlett.4c00444

Jenson R. Feys, Kyle Edwards, Michael A. Joyce, Holly A. Saffran, Justin A. Shields, Kassandra Garcia, D. Lorne Tyrrell and Conrad Fischer*,

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Abstract

The main protease of SARS-CoV-2 is an essential enzyme required for polyprotein cleavage during viral replication and thus is an excellent target for development of direct-acting antiviral compounds. Continued research efforts have elucidated several peptidic small molecules like GC376, boceprevir, and nirmatrelvir with potent anticoronaviral activity bearing optimized amino acid side chain residues. To reduce synthetic complexity and cost, we used simple chemical surrogates that were commercially readily available to develop new inhibitors that mimic the potency of these drug compounds. We synthesized and tested several analogue chimeras of GC376 and boceprevir that have surrogate residues at the P1 and/or P2 position in order to further improve target binding. Both P1 variants with either a nonpolar cyclobutyl or polar thiazol-4-yl alanine resulted in low-micromolar to submicromolar M^pro inhibitors with strong antiviral activity in cell assays.

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含有噻唑-4-基丙氨酸的肽醛是 SARS-CoV-2 主要蛋白酶的强效体外抑制剂

SARS-CoV-2 的主要蛋白酶是病毒复制过程中多蛋白裂解所需的重要酶，因此是开发直接作用抗病毒化合物的绝佳靶点。通过持续的研究工作，我们已经阐明了几种多肽小分子（如 GC376、boceprevir 和 nirmatrelvir），它们具有强效的抗oronaviral 活性，并具有优化的氨基酸侧链残基。为了降低合成的复杂性和成本，我们利用市场上容易买到的简单化学代用品来开发新的抑制剂，以模仿这些药物化合物的效力。我们合成并测试了几种 GC376 和 boceprevir 的类似嵌合体，这些嵌合体在 P1 和/或 P2 位置具有代用残基，以进一步改善靶标结合。这两种 P1 变体都带有非极性环丁基或极性噻唑-4-基丙氨酸，从而产生了低微摩至亚微摩尔的 Mpro 抑制剂，在细胞实验中具有很强的抗病毒活性。

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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.