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天然化合物抑制新型冠状病毒nsp13解旋和ATP酶活性。

Natural Compounds Inhibit SARS-CoV-2 nsp13 Unwinding and ATPase Enzyme Activities.

作者信息

Corona Angela, Wycisk Krzysztof, Talarico Carmine, Manelfi Candida, Milia Jessica, Cannalire Rolando, Esposito Francesca, Gribbon Philip, Zaliani Andrea, Iaconis Daniela, Beccari Andrea R, Summa Vincenzo, Nowotny Marcin, Tramontano Enzo

机构信息

Dipartimento di Scienze della vita e dell'ambiente, Università degli Studi di Cagliari, Cittadella Universitaria di Monserrato, SS-554, 09042 Monserrato, Cagliari, Italy.

Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, Ks. Trojdena 4, Warsaw 02-109, Poland.

出版信息

ACS Pharmacol Transl Sci. 2022 Apr 1;5(4):226-239. doi: 10.1021/acsptsci.1c00253. eCollection 2022 Apr 8.

DOI:10.1021/acsptsci.1c00253
PMID:35434533
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9003574/
Abstract

SARS-CoV-2 infection is still spreading worldwide, and new antiviral therapies are an urgent need to complement the approved vaccine preparations. SARS-CoV-2 nps13 helicase is a validated drug target participating in the viral replication complex and possessing two associated activities: RNA unwinding and 5'-triphosphatase. In the search of SARS-CoV-2 direct antiviral agents, we established biochemical assays for both SARS-CoV-2 nps13-associated enzyme activities and screened both and a small in-house library of natural compounds. Myricetin, quercetin, kaempferol, and flavanone were found to inhibit the SARS-CoV-2 nps13 unwinding activity at nanomolar concentrations, while licoflavone C was shown to block both SARS-CoV-2 nps13 activities at micromolar concentrations. Mode of action studies showed that all compounds are nsp13 noncompetitive inhibitors versus ATP, while computational studies suggested that they can bind both nucleotide and 5'-RNA nsp13 binding sites, with licoflavone C showing a unique pattern of interaction with nsp13 amino acid residues. Overall, we report for the first time natural flavonoids as selective inhibitors of SARS-CoV-2 nps13 helicase with low micromolar activity.

摘要

严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染仍在全球范围内传播，因此迫切需要新的抗病毒疗法来补充已获批的疫苗制剂。SARS-CoV-2 nps13解旋酶是一个经过验证的药物靶点，参与病毒复制复合体，并具有两种相关活性：RNA解旋和5'-三磷酸酶活性。在寻找SARS-CoV-2直接抗病毒药物的过程中，我们针对SARS-CoV-2 nps13相关的两种酶活性建立了生化检测方法，并对内部一个小型天然化合物库进行了筛选。发现杨梅素、槲皮素、山奈酚和黄烷酮在纳摩尔浓度下可抑制SARS-CoV-2 nps13的解旋活性，而甘草黄酮C在微摩尔浓度下可阻断SARS-CoV-2 nps13的两种活性。作用机制研究表明，所有化合物都是nsp13对ATP的非竞争性抑制剂，而计算研究表明它们可以结合核苷酸和5'-RNA nsp13结合位点，甘草黄酮C与nsp13氨基酸残基的相互作用呈现出独特的模式。总体而言，我们首次报道天然黄酮类化合物是具有低微摩尔活性的SARS-CoV-2 nps13解旋酶的选择性抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/217a/9003574/c54c2363ab51/pt1c00253_0010.jpg
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