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      Therapeutic strategies for COVID-19: progress and lessons learned

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          Abstract

          The coronavirus disease 2019 (COVID-19) pandemic has stimulated tremendous efforts to develop therapeutic strategies that target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and/or human proteins to control viral infection, encompassing hundreds of potential drugs and thousands of patients in clinical trials. So far, a few small-molecule antiviral drugs (nirmatrelvir–ritonavir, remdesivir and molnupiravir) and 11 monoclonal antibodies have been marketed for the treatment of COVID-19, mostly requiring administration within 10 days of symptom onset. In addition, hospitalized patients with severe or critical COVID-19 may benefit from treatment with previously approved immunomodulatory drugs, including glucocorticoids such as dexamethasone, cytokine antagonists such as tocilizumab and Janus kinase inhibitors such as baricitinib. Here, we summarize progress with COVID-19 drug discovery, based on accumulated findings since the pandemic began and a comprehensive list of clinical and preclinical inhibitors with anti-coronavirus activities. We also discuss the lessons learned from COVID-19 and other infectious diseases with regard to drug repurposing strategies, pan-coronavirus drug targets, in vitro assays and animal models, and platform trial design for the development of therapeutics to tackle COVID-19, long COVID and pathogenic coronaviruses in future outbreaks.

          Abstract

          Since the COVID-19 pandemic began, many potential therapeutics that target SARS-CoV-2 and/or human proteins to control viral infection have been investigated, with a few receiving authorization by regulatory agencies. This Review article summarizes progress with COVID-19 drug discovery, and discusses the lessons learned about aspects such as drug repurposing, disease models and clinical development strategies.

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          Most cited references290

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          A Novel Coronavirus from Patients with Pneumonia in China, 2019

          Summary In December 2019, a cluster of patients with pneumonia of unknown cause was linked to a seafood wholesale market in Wuhan, China. A previously unknown betacoronavirus was discovered through the use of unbiased sequencing in samples from patients with pneumonia. Human airway epithelial cells were used to isolate a novel coronavirus, named 2019-nCoV, which formed a clade within the subgenus sarbecovirus, Orthocoronavirinae subfamily. Different from both MERS-CoV and SARS-CoV, 2019-nCoV is the seventh member of the family of coronaviruses that infect humans. Enhanced surveillance and further investigation are ongoing. (Funded by the National Key Research and Development Program of China and the National Major Project for Control and Prevention of Infectious Disease in China.)
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            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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              Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

              Abstract Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)
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                Author and article information

                Contributors
                liguangdi.research@gmail.com
                rolf.hilgenfeld@uni-luebeck.de
                rwhitley@uabmc.edu
                erik.declercq@kuleuven.be
                Journal
                Nat Rev Drug Discov
                Nat Rev Drug Discov
                Nature Reviews. Drug Discovery
                Nature Publishing Group UK (London )
                1474-1776
                1474-1784
                19 April 2023
                : 1-27
                Affiliations
                [1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Xiangya School of Public Health, , Central South University; Hunan Children’s Hospital, ; Changsha, China
                [2 ]GRID grid.4562.5, ISNI 0000 0001 0057 2672, Institute of Molecular Medicine & German Center for Infection Research (DZIF), , University of Lübeck, ; Lübeck, Germany
                [3 ]GRID grid.265892.2, ISNI 0000000106344187, Department of Paediatrics, Microbiology, Medicine and Neurosurgery, , University of Alabama at Birmingham, ; Birmingham, AL USA
                [4 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, , KU Leuven, ; Leuven, Belgium
                Author information
                http://orcid.org/0000-0001-8852-034X
                http://orcid.org/0000-0001-8850-2977
                http://orcid.org/0000-0001-9959-9276
                http://orcid.org/0000-0002-2985-8890
                Article
                672
                10.1038/s41573-023-00672-y
                10113999
                37076602
                98fa240d-09e2-452d-9222-a35ad788ea55
                © Springer Nature Limited 2023, Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                History
                : 28 February 2023
                Categories
                Review Article

                antiviral agents,sars-cov-2,antivirals
                antiviral agents, sars-cov-2, antivirals

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