Identification and Evaluation of Non-Nucleosidic MTase Inhibitors against SARS-CoV-2 nsp14 with Lower-Micromolar Anti-Coronavirus Activity.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-07-17 DOI:10.1021/acsinfecdis.4c01044

Yuanmei Wen, Jun Zhou, Fan Pan, Peisen Zheng, Fengxia Zhong, Sidi Yang, Qianhan Ma, Deyin Guo, Xumu Zhang, Qifan Zhou, Yingjun Li

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引用次数: 0

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key N7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC₅₀ = 21.6 μM) and binding affinity (ΔT_m = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC₅₀ = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.

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具有低微摩尔抗冠状病毒活性的SARS-CoV-2 nsp14非核苷类MTase抑制剂的鉴定和评价

严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）引起轻度至重度呼吸道感染，构成重大公共卫生风险。新变异的出现突出表明需要针对保守的非结构蛋白（如nsp14）的抑制剂，nsp14是一种关键的n7甲基转移酶（MTase），对病毒RNA盖帽、免疫逃避和复制至关重要。在这里，我们使用药物再利用方法筛选了131种化合物，并确定了5种抑制MTase活性的候选化合物。Bobcat339表现出显著的抑制作用（IC50 = 21.6 μM）和结合亲和力（ΔTm = +3.9°C）。HCoV-229E和SARS-CoV-2在感染的Huh7细胞中的复制也降低（EC50分别为29.8 μM和28.4 μM）。分子对接表明Bobcat339结合了nsp14 MTase的sam结合袋。这些结果确定Bobcat339是开发选择性非核苷类nsp14抑制剂的有希望的先导物，支持进一步的结构优化和临床前评估。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.