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高通量筛选发现抑制 SARS-CoV-2 Mac1-ADP-ribose 结合的化合物。

Discovery of compounds that inhibit SARS-CoV-2 Mac1-ADP-ribose binding by high-throughput screening.

机构信息

Infectious Disease Assay Development Laboratory/HTS, University of Kansas, Lawrence, KS, 66047, USA.

Department of Molecular Biosciences, University of Kansas, Lawrence, KS, 66045, USA.

出版信息

Antiviral Res. 2022 Jul;203:105344. doi: 10.1016/j.antiviral.2022.105344. Epub 2022 May 19.

DOI:10.1016/j.antiviral.2022.105344
PMID:35598780
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9119168/
Abstract

The emergence of several zoonotic viruses in the last twenty years, especially the pandemic outbreak of SARS-CoV-2, has exposed a dearth of antiviral drug therapies for viruses with pandemic potential. Developing a diverse drug portfolio will be critical to rapidly respond to novel coronaviruses (CoVs) and other viruses with pandemic potential. Here we focus on the SARS-CoV-2 conserved macrodomain (Mac1), a small domain of non-structural protein 3 (nsp3). Mac1 is an ADP-ribosylhydrolase that cleaves mono-ADP-ribose (MAR) from target proteins, protects the virus from the anti-viral effects of host ADP-ribosyltransferases, and is critical for the replication and pathogenesis of CoVs. In this study, a luminescent-based high-throughput assay was used to screen ∼38,000 small molecules for those that could inhibit Mac1-ADP-ribose binding. We identified 5 compounds amongst 3 chemotypes that inhibit SARS-CoV-2 Mac1-ADP-ribose binding in multiple assays with IC values less than 100 μM, inhibit ADP-ribosylhydrolase activity, and have evidence of direct Mac1 binding. These chemotypes are strong candidates for further derivatization into highly effective Mac1 inhibitors.

摘要

在过去的二十年中，出现了几种人畜共患病毒，特别是 SARS-CoV-2 的大流行爆发，暴露了针对具有大流行潜力的病毒缺乏抗病毒药物治疗方法。开发多样化的药物组合对于快速应对新型冠状病毒（CoV）和其他具有大流行潜力的病毒将至关重要。在这里，我们重点关注 SARS-CoV-2 的保守宏结构域（Mac1），这是一种非结构蛋白 3（nsp3）的小结构域。Mac1 是一种 ADP-核糖基水解酶，可从靶蛋白中切割单 ADP-核糖（MAR），保护病毒免受宿主 ADP-核糖基转移酶的抗病毒作用的影响，并且对 CoV 的复制和发病机制至关重要。在这项研究中，使用基于发光的高通量测定法筛选了约 38,000 种小分子，以鉴定那些可以抑制 Mac1-ADP-核糖结合的小分子。我们在多种测定中鉴定了 3 种化学型中的 5 种化合物，这些化合物可以抑制 SARS-CoV-2 Mac1-ADP-核糖结合，IC 值小于 100 μM，抑制 ADP-核糖基水解酶活性，并具有直接与 Mac1 结合的证据。这些化学型是进一步衍生为高效 Mac1 抑制剂的有力候选者。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/c697d97cf507/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/ca1ce6d6ce47/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/a43655dd77d7/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/c362acf9fd46/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/337131c35092/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/89326394bbe9/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/7969073ba7e9/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/e23bd357d302/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/f65cd6bd5a98/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/c697d97cf507/gr8_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/ca1ce6d6ce47/ga1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/a43655dd77d7/gr1_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/c362acf9fd46/gr2_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/337131c35092/gr3_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/89326394bbe9/gr4_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/7969073ba7e9/gr5_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/e23bd357d302/gr6_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/f65cd6bd5a98/gr7_lrg.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7070/9119168/c697d97cf507/gr8_lrg.jpg

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