Identification of potent inhibitors of SARS-CoV-2 infection by combined pharmacological evaluation and cellular network prioritization.
Identification of potent inhibitors of SARS-CoV-2 infection by combined pharmacological evaluation and cellular network prioritization.
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DOI：
10.1016/j.isci.2022.104925
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发表时间：
2022-09-16
期刊：
影响因子：
5.8
通讯作者：
Davey, Robert A.
中科院分区：
文献类型：
--
作者：
Patten, J. J.;Keiser, Patrick T.;Morselli-Gysi, Deisy;Menichetti, Giulia;Mori, Hiroyuki;Donahue, Callie J.;Gan, Xiao;do Valle, Italo;Geoghegan-Barek, Kathleen;Anantpadma, Manu;Boytz, RuthMabel;Berrigan, Jacob L.;Stubbs, Sarah H.;Ayazika, Tess;O'Leary, Colin;Jalloh, Sallieu;Wagner, Florence;Ayehunie, Seyoum;Elledge, Stephen J.;Anderson, Deborah;Loscalzo, Joseph;Zitnik, Marinka;Gummuluru, Suryaram;Namchuk, Mark N.;Barabasi, Albert-Laszlo;Davey, Robert A.
在细胞和组织模型中，评估了具有已知生物靶点的药理活性化合物对SARS-CoV-2感染的抑制作用，以帮助识别有效的活性小分子类别，并更好地了解宿主与病毒的相互作用。我们评估了6,710个针对2,183个宿主蛋白的临床和临床前化合物，通过基于免疫细胞荧光的筛选来识别SARS-CoV-2感染抑制剂。通过计算整合小分子结构、剂量-反应抗病毒活性、宿主靶标和细胞相互作用体之间的关系，产生了对感染重要的细胞网络。这项分析揭示了389个具有微摩尔到低纳摩尔活性的小分子，代表了12个支架类别和813个宿主目标。在SARS-CoV-2变种和MERS-CoV的稳定和原代人类细胞模型中，对代表性的作用机制进行了评估。一种有希望的候选药物obtoclax显著降低了小鼠的SARS-CoV-2病毒载量。最终，这项工作为未来对宿主因子依赖性和病毒疾病治疗的药理学和计算鉴定建立了一种严格的方法。鉴定了389种SARS-CoV-2抑制剂，包括12个结构相似的基团药物-蛋白质靶标网络分析揭示宿主依赖性稳定和原代细胞培养中病毒变异的机制评估主要候选者降低小鼠疾病模型中的病毒肺负荷生物信息学；药物信息学；药理学；病毒学
Pharmacologically active compounds with known biological targets were evaluated for inhibition of SARS-CoV-2 infection in cell and tissue models to help identify potent classes of active small molecules and to better understand host-virus interactions. We evaluated 6,710 clinical and preclinical compounds targeting 2,183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target, and cell interactome produced cellular networks important for infection. This analysis revealed 389 small molecules with micromolar to low nanomolar activities, representing >12 scaffold classes and 813 host targets. Representatives were evaluated for mechanism of action in stable and primary human cell models with SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of host factor dependencies and treatments for viral diseases. Identified 389 SARS-CoV-2 inhibitors comprising >12 structurally similar groups Drug-protein target network analyses reveal host dependencies Mechanistic evaluation of virus variants in stable and primary cell cultures Lead candidate decreases virus lung load in mouse model of disease Bioinformatics; Pharmacoinformatics; Pharmacology; Virology
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影响因子：
16.6
作者：
Akiyama H;Miller CM;Ettinger CR;Belkina AC;Snyder-Cappione JE;Gummuluru S
通讯作者：
Gummuluru S
影响因子：
8.8
作者：
Dittmar M;Lee JS;Whig K;Segrist E;Li M;Kamalia B;Castellana L;Ayyanathan K;Cardenas-Diaz FL;Morrisey EE;Truitt R;Yang W;Jurado K;Samby K;Ramage H;Schultz DC;Cherry S
通讯作者：
Cherry S
DOI：
10.1073/pnas.2025581118
发表时间：
2021-05-11
影响因子：
11.1
作者：
Morselli Gysi D;do Valle Í;Zitnik M;Ameli A;Gan X;Varol O;Ghiassian SD;Patten JJ;Davey RA;Loscalzo J;Barabási AL
通讯作者：
Barabási AL
影响因子：
4.9
作者：
Gunesch, Antonia P.;Zapatero-Belinchon, Francisco J.;von Hahn, Thomas
通讯作者：
von Hahn, Thomas
影响因子：
56.9
作者：
Lamers, Mart M.;Beumer, Joep;Clevers, Hans
通讯作者：
Clevers, Hans