Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing.
Laura Riva,Shuofeng Yuan,Xin Yin,Laura Martin-Sancho,Naoko Matsunaga,Lars Pache,Sebastian Burgstaller-Muehlbacher,Paul D. De Jesus,Peter Teriete,Mitchell V. Hull,Max W. Chang,Jasper Fuk-Woo Chan,Jianli Cao,Vincent Kwok-Man Poon,Kristina M. Herbert,Kuoyuan Cheng,Kuoyuan Cheng,Tu Trinh H. Nguyen,Andrey Rubanov,Yuan Pu,Courtney Nguyen,Angela Choi,Raveen Rathnasinghe,Michael Schotsaert,Lisa Miorin,Marion Dejosez,Thomas P. Zwaka,Ko Yung Sit,Luis Martinez-Sobrido,Wen-Chun Liu,Kris M. White,Mackenzie E. Chapman,Emma K. Lendy,Richard Glynne,Randy A. Albrecht,Eytan Ruppin,Andrew D. Mesecar,Jeffrey R Johnson,Christopher Benner,Ren Sun,Peter G. Schultz,Andrew I. Su,Adolfo García-Sastre,Arnab K. Chatterjee,Kwok-Yung Yuen,Sumit K. Chanda +45 more
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TLDR
A screen of the ReFRAME library of approximately 12,000 known drugs for antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identified several candidate compounds with suitable activities and pharmacological profiles, which could potentially expedite the deployment of therapies for coronav virus disease 2019 (COVID-19).Abstract:
The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12–18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose–response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2–4 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 pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod 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, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19. A screen of the ReFRAME library of approximately 12,000 known drugs for antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) identified several candidate compounds with suitable activities and pharmacological profiles, which could potentially expedite the deployment of therapies for coronavirus disease 2019 (COVID-19).read more
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The BioGRID database: A comprehensive biomedical resource of curated protein, genetic, and chemical interactions.
Rose Oughtred,Jennifer M. Rust,Christie S. Chang,Bobby-Joe Breitkreutz,Chris Stark,Andrew Willems,Lorrie Boucher,Genie Leung,Nadine Kolas,Frederick Zhang,Sonam Dolma,Jasmin Coulombe-Huntington,Andrew Chatr-aryamontri,Kara Dolinski,Mike Tyers,Mike Tyers +15 more
TL;DR: The BioGRID (Biological General Repository for Interaction Datasets, thebiogrid.org) is an open‐access database resource that houses manually curated protein and genetic interactions from multiple species including yeast, worm, fly, mouse, and human.
Journal ArticleDOI
Identification of Required Host Factors for SARS-CoV-2 Infection in Human Cells.
Zharko Daniloski,Tristan X. Jordan,Hans-Hermann Wessels,Daisy A. Hoagland,Silva Kasela,Mateusz Legut,Silas Maniatis,Eleni P. Mimitou,Lu Lu,Evan T. Geller,Oded Danziger,Brad R. Rosenberg,Hemali Phatnani,Peter Smibert,Tuuli Lappalainen,Benjamin R. tenOever,Neville E. Sanjana +16 more
TL;DR: Overall, this work provides a genome-scale, quantitative resource of the impact of the loss of each host gene on fitness/response to viral infection.
Journal ArticleDOI
Genetic Screens Identify Host Factors for SARS-CoV-2 and Common Cold Coronaviruses.
Ruofan Wang,Camille R. Simoneau,Jessie Kulsuptrakul,Mehdi Bouhaddou,Katherine A. Travisano,Jennifer M. Hayashi,Jennifer M. Hayashi,Jared Carlson-Stevermer,James Zengel,Christopher M. Richards,Parinaz Fozouni,Jennifer Oki,Lauren Rodriguez,Bastian Joehnk,Keith Walcott,Kevin Holden,Anita Sil,Jan E. Carette,Nevan J. Krogan,Melanie Ott,Melanie Ott,Andreas S. Puschnik +21 more
TL;DR: Pharmacological inhibition of phosphatidylinositol kinases and cholesterol homeostasis reduced replication of all three coronaviruses and offer important insights for the understanding of the coronavirus life cycle and the development of host-directed therapies.
Journal ArticleDOI
SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response
Jessie Huang,Jessie Huang,Adam J. Hume,Kristine M. Abo,Kristine M. Abo,Rhiannon B. Werder,Rhiannon B. Werder,Rhiannon B. Werder,Carlos Villacorta-Martin,Konstantinos-Dionysios Alysandratos,Konstantinos-Dionysios Alysandratos,Mary Lou Beermann,Mary Lou Beermann,Chantelle Simone-Roach,Chantelle Simone-Roach,Jonathan Lindstrom-Vautrin,Judith Olejnik,Ellen L Suder,Esther Bullitt,Anne Hinds,Arjun Sharma,Markus Bosmann,Ruobing Wang,Ruobing Wang,Ruobing Wang,Finn Hawkins,Finn Hawkins,Eric J. Burks,Mohsan Saeed,Andrew A. Wilson,Andrew A. Wilson,Elke Mühlberger,Darrell N. Kotton,Darrell N. Kotton +33 more
TL;DR: An in vitro human model that simulates the initial apical infection of alveolar epithelium with SARS-CoV-2 is presented, using induced pluripotent stem cell-derived AT2s that have been adapted to air-liquid interface culture and finds a rapid transcriptomic change in infected cells, characterized by a shift to an inflammatory phenotype with upregulation of NF-kB signaling and loss of the matureAlveolar program.
Journal ArticleDOI
Network medicine framework for identifying drug-repurposing opportunities for COVID-19.
Deisy Morselli Gysi,Deisy Morselli Gysi,Italo Faria do Valle,Marinka Zitnik,Asher Ameli,Xiao Gan,Xiao Gan,Onur Varol,Helia N. Sanchez,Rebecca M. Baron,Dina Ghiassian,Joseph Loscalzo,Albert-László Barabási,Albert-László Barabási,Albert-László Barabási +14 more
TL;DR: In this article, the authors deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2.
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TL;DR: The clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia who were admitted to the intensive care unit (ICU) of Wuhan Jin Yin-tan hospital between late December, 2019 and Jan 26, 2020 are described.
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