Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Riva, Laura; Yuan, Shuofeng; Yin, Xin; Martin-Sancho, Laura; Matsunaga, Naoko; Pache, Lars; Burgstaller-Muehlbacher, Sebastian; Jesus, Paul D. De; Teriete, Peter; Hull, Mitchell V.; Chang, Max W.; Chan, Jasper Fuk Woo; Cao, Jianli; Poon, Vincent Kwok Man; Herbert, Kristina M.; Cheng, Kuoyuan; Nguyen, Tu; Rubanov, Andrey; Pu, Yuan; Nguyen, Calvin; Choi, Angela; Rathnasinghe, Raveen; Schotsaert, Michael; Miorin, Lisa; Déjosez, Marion; Zwaka, Thomas P.; Sit, Ko Yung; Martínez-Sobrido, Luis; Liu, Wen Chun; White, Kris M.; Chapman, Mackenzie E.; Lendy, Emma K.; Glynne, Richard; Albrecht, Randy A.; Ruppin, Eytan; Mesecar, Andrew D.; Johnson, Jeffrey R.; Benner, Christopher; Sun, Ren; Schultz, Peter G.; Su, Andrew I.; Garcı́a-Sastre, Adolfo; Chatterjee, Arnab K.; Yuen, Kwok Yung; Chanda, Sumit K.

doi:10.1038/s41586-020-2577-1

Cited by 756 publications

(824 citation statements)

References 65 publications

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“…Our results also inform those of a recent drug repurposing screen, which identified ~100 compounds that inhibited SARS-CoV-2 replication 64 ; notably, among those were PIKfyve inhibitors, protease inhibitors and modulators of cholesterol homeostasis. Our functional genomics data therefore suggest that the observed effects of several compounds were possibly due to inhibition of critical host factors.…”

Section: Discussionsupporting

confidence: 81%

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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The Coronaviridae are a family of viruses that causes disease in humans ranging from mild respiratory infection to potentially lethal acute respiratory distress syndrome. Finding host factors that are common to multiple coronaviruses could facilitate the development of therapies to combat current and future coronavirus pandemics. Here, we conducted parallel genome-wide CRISPR screens in cells infected by SARS-CoV-2 as well as two seasonally circulating common cold coronaviruses, OC43 and 229E. This approach correctly identified the distinct viral entry factors ACE2 (for SARS-CoV-2), aminopeptidase N (for 229E) and glycosaminoglycans (for OC43). Additionally, we discovered phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis as critical host pathways supporting infection by all three coronaviruses. By contrast, the lysosomal protein TMEM106B appeared unique to SARS-CoV-2 infection. Pharmacological inhibition of phosphatidylinositol phosphate biosynthesis and cholesterol homeostasis reduced replication of all three coronaviruses. These findings offer important insights for the understanding of the coronavirus life cycle as well as the potential development of host-directed therapies.

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Section: Discussionsupporting

confidence: 81%

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Wang

Simoneau

Kulsuptrakul

et al. 2020

Preprint

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“…One obvious way to speed up drug discovery is through the use of drug-repurposing screens, looking to identify safe-in-human drugs with potential anti-coronavirus properties 9,13,14 . Here, we employed a three-tiered approach for drug repurposing, to identify potential broad-spectrum anticoronavirus drugs that specifically target the viral main protease, 3CLpro.…”

Section: Introductionmentioning

confidence: 99%

Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2in vitro

Drayman

Jones

Azizi

et al. 2020

Preprint

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There is an urgent need for anti-viral agents that treat SARS-CoV-2 infection. The shortest path to clinical use is repurposing of drugs that have an established safety profile in humans. Here, we first screened a library of 1,900 clinically safe drugs for inhibiting replication of OC43, a human beta-coronavirus that causes the common-cold and is a relative of SARS-CoV-2, and identified 108 effective drugs. We further evaluated the top 26 hits and determined their ability to inhibit SARS-CoV-2, as well as other pathogenic RNA viruses. 20 of the 26 drugs significantly inhibited SARS-CoV-2 replication in human lung cells (A549 epithelial cell line), with EC50 values ranging from 0.1 to 8 micromolar. We investigated the mechanism of action for these and found that masitinib, a drug originally developed as a tyrosine-kinase inhibitor for cancer treatment, strongly inhibited the activity of the SARS-CoV-2 main protease 3CLpro. X-ray crystallography revealed that masitinib directly binds to the active site of 3CLpro, thereby blocking its enzymatic activity. Mastinib also inhibited the related viral protease of picornaviruses and blocked picornaviruses replication. Thus, our results show that masitinib has broad anti-viral activity against two distinct beta-coronaviruses and multiple picornaviruses that cause human disease and is a strong candidate for clinical trials to treat SARS-CoV-2 infection.

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“…The raging pandemic caused by SARS-CoV-2 requires a rapid response of the biomedical community 1,2 . However, novel vaccines and antivirals require time for development, thus repurposing of available drugs is a fast alternative and many attempts using different approaches are made [3][4][5][6] . Antiviral drugs are traditionally aimed at viral enzymes and are able to cure or reduce symptoms in several viral infections (HIV, HCV and HSV-1 7 ).…”

Section: Introductionmentioning

confidence: 99%

Conserved interactions required for in vitro inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Shitrit

Zaidman

Kalid³

et al. 2020

Preprint

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The COVID-19 pandemic caused by the SARS-CoV-2 requires a fast development of antiviral drugs. SARS-CoV-2 viral main protease (Mpro, also called 3C-like protease, 3CLpro) is a potential target for drug design. Crystal and co-crystal structures of the SARS-CoV-2 Mpro have been solved, enabling the rational design of inhibitory compounds. In this study we analyzed the available SARS-CoV-2 and the highly similar SARS-CoV-1 crystal structures. We identified within the active site of the Mpro, in addition to the inhibitory ligands’ interaction with the catalytic C145, two key H-bond interactions with the conserved H163 and E166 residues. Both H-bond interactions are present in almost all co-crystals and are likely to occur also during the viral polypeptide cleavage process as suggested from docking of the Mpro cleavage recognition sequence. We screened in silico a library of 6,900 FDA-approved drugs (ChEMBL) and filtered using these key interactions and selected 29 non-covalent compounds predicted to bind to the protease. Additional screen, using DOCKovalent was carried out on DrugBank library (11,414 experimental and approved drugs) and resulted in 6 covalent compounds. The selected compounds from both screens were tested in vitro by a protease activity inhibition assay. Two compounds showed activity at the 50μM concentration range. Our analysis and findings can facilitate and focus the development of highly potent inhibitors against SARS-CoV-2 infection.

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Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing

Cited by 756 publications

References 65 publications

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Functional genomic screens identify human host factors for SARS-CoV-2 and common cold coronaviruses

Drug repurposing screen identifies masitinib as a 3CLpro inhibitor that blocks replication of SARS-CoV-2in vitro

Conserved interactions required for in vitro inhibition of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

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