德国自由电子激光科学中心Alke Meents、Sebastian Günther等研究人员合作，利用X射线筛选发现SARS-CoV-2主要蛋白酶的活性位点和变构抑制剂。相关论文于2021年4月2日在线发表在《科学》杂志上。
在寻找针对COVID-19的药物时，研究人员对两种靶向SARS-CoV-2主蛋白酶（Mpro）的再利用药物库进行了高通量X射线晶体学筛选，这个蛋白酶对于病毒复制至关重要。与复杂度低分子通常使用的X射线碎片筛选实验相反，这个筛选方法是对已获批准的药物和临床试验中的药物进行测试。
从三维蛋白质结构中，研究人员确定了37种与Mpro结合的化合物。在随后细胞病毒测定中，一种拟肽和六种非肽化合物在无毒浓度下显示出抗病毒活性。研究人员确定了两个变构结合位点，这是可用于SARS-CoV-2药物开发的潜在靶点。
COVID-19正在给人类带来巨大挑战。迄今为止，尚无有效药物可直接治疗该疾病。
附：英文原文
Title: X-ray screening identifies active site and allosteric inhibitors of SARS-CoV-2 main protease
Author: Sebastian Günther, Patrick Y. A. Reinke, Yaiza Fernández-García, Julia Lieske, Thomas J. Lane, Helen M. Ginn, Faisal H. M. Koua, Christiane Ehrt, Wiebke Ewert, Dominik Oberthuer, Oleksandr Yefanov, Susanne Meier, Kristina Lorenzen, Boris Krichel, Janine-Denise Kopicki, Luca Gelisio, Wolfgang Brehm, Ilona Dunkel, Brandon Seychell, Henry Gieseler, Brenna Norton-Baker, Beatriz Escudero-Pérez, Martin Domaracky, Sofiane Saouane, Alexandra Tolstikova, Thomas A. White, Anna Hnle, Michael Groessler, Holger Fleckenstein, Fabian Trost, Marina Galchenkova, Yaroslav Gevorkov, Chufeng Li, Salah Awel, Ariana Peck, Miriam Barthelmess, Frank Schluenzen, Paulraj Lourdu Xavier, Nadine Werner, Hina Andaleeb, Najeeb Ullah, Sven Falke, Vasundara Srinivasan, Bruno Alves Frana, Martin Schwinzer, Hévila Brognaro, Cromarte Rogers, Diogo Melo, Joanna J. Zaitseva-Doyle, Juraj Knoska, Gisel E. Pea-Murillo, Aida Rahmani Mashhour, Vincent Hennicke, Pontus Fischer, Johanna Hakanp, Jan Meyer, Philip Gribbon, Bernhard Ellinger, Maria Kuzikov, Markus Wolf, Andrea R. Beccari, Gleb Bourenkov, David von Stetten, Guillaume Pompidor, Isabel Bento, Saravanan Panneerselvam, Ivars Karpics, Thomas R. Schneider, Maria Marta Garcia-Alai, Stephan Niebling
Issue&Volume: 2021/04/02
Abstract: The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput X-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (Mpro), which is essential for viral replication. In contrast to commonly applied X-ray fragment screening experiments with molecules of low complexity, our screen tested already approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to Mpro. In subsequent cell-based viral reduction assays, one peptidomimetic and six non-peptidic compounds showed antiviral activity at non-toxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2.
DOI: 10.1126/science.abf7945
Source: https://science.sciencemag.org/content/early/2021/03/31/science.abf7945