Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
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DOI：
10.1038/s41586-020-2577-1
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发表时间：
2020-10
期刊：
影响因子：
64.8
通讯作者：
Chanda SK
中科院分区：
文献类型：
--
作者：
Riva L;Yuan S;Yin X;Martin-Sancho L;Matsunaga N;Pache L;Burgstaller-Muehlbacher S;De Jesus PD;Teriete P;Hull MV;Chang MW;Chan JF;Cao J;Poon VK;Herbert KM;Cheng K;Nguyen TH;Rubanov A;Pu Y;Nguyen C;Choi A;Rathnasinghe R;Schotsaert M;Miorin L;Dejosez M;Zwaka TP;Sit KY;Martinez-Sobrido L;Liu WC;White KM;Chapman ME;Lendy EK;Glynne RJ;Albrecht R;Ruppin E;Mesecar AD;Johnson JR;Benner C;Sun R;Schultz PG;Su AI;García-Sastre A;Chatterjee AK;Yuen KY;Chanda SK
2019年新型严重急性呼吸综合征冠状病毒2型（SARS-CoV - 2）的出现引发了一场持续的全球大流行，这种类似严重肺炎的疾病被命名为2019冠状病毒病（COVID - 19）。疫苗的研发可能至少需要12 - 18个月，而一种新型抗病毒治疗药物获得批准的典型时间可能超过10年。因此，对已知药物进行重新利用可能会显著加快针对COVID - 19的新型疗法的应用。为此，我们对一个包含约12000种处于临床阶段或已获美国食品药品监督管理局（FDA）批准的小分子药物库进行了分析。我们报告鉴定出了100种抑制病毒复制的分子，其中包括21种呈现剂量 - 反应关系的已知药物。在这些药物中，有13种被发现其有效浓度可能与患者可达到的治疗剂量相当，包括PIKfyve激酶抑制剂阿匹莫德，以及半胱氨酸蛋白酶抑制剂MDL - 28170、Z LVG CHN2、VBY - 825和ONO 5334。值得注意的是，发现MDL - 28170、ONO 5334和阿匹莫德可拮抗人诱导多能干细胞衍生的肺细胞样细胞中的病毒复制，并且PIKfyve抑制剂在原代人肺外植体模型中也显示出抗病毒功效。由于本研究中鉴定出的大多数分子已经进入临床阶段，这些化合物已知的药理学和人体安全性特征将使这些药物针对COVID - 19治疗的临床前和临床评估得以加速进行。
The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19). The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod, and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.
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DOI：
10.1073/pnas.1810137115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
通讯作者：
Chatterjee AK
影响因子：
5.4
作者：
Chen, Wen-Hsiang;Strych, Ulrich;Bottazzi, Maria Elena
通讯作者：
Bottazzi, Maria Elena
影响因子：
5.9
作者：
Cihlar, Tomas;Fordyce, Marshall
通讯作者：
Fordyce, Marshall
影响因子：
168.9
作者：
Chan, Jasper Fuk-Woo;Yuan, Shuofeng;Yuen, Kwok-Yung
通讯作者：
Yuen, Kwok-Yung
DOI：
10.1164/rccm.201911-2199oc
发表时间：
2020-12-15
影响因子：
24.7
作者：
Deprez, Marie;Zaragosi, Laure-Emmanuelle;Barbry, Pascal
通讯作者：
Barbry, Pascal