“…In theory, there is potential to develop pan-coronavirus inhibitors that target drug-binding pockets with highly conserved sequences and structures across multiple coronaviruses. Preclinical studies have indicated the pan-coronavirus potential of NSP12 inhibitors such as remdesivir 257 , molnupiravir 115 and 6-72-2a 258 in cell culture and/or animal models. The M pro inhibitors such as nirmatrelvir 78 , ensitrelvir 86 and GC376 (ref.…”
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.
“…In theory, there is potential to develop pan-coronavirus inhibitors that target drug-binding pockets with highly conserved sequences and structures across multiple coronaviruses. Preclinical studies have indicated the pan-coronavirus potential of NSP12 inhibitors such as remdesivir 257 , molnupiravir 115 and 6-72-2a 258 in cell culture and/or animal models. The M pro inhibitors such as nirmatrelvir 78 , ensitrelvir 86 and GC376 (ref.…”
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.
“…Compound 7h (R 1 = H, R 2 = Boc, R 3 = 3-EtOC6H 4 ) represented the most promising agent (EC 50 = 1.41 μM, selectivity index = >70.92). However, the other compounds showed good to mild RdRp inhibition effect with an EC 50 = 1.70, 2.75, 2.53, 3.07, 1.05 μM for 7e (R 1 = R 2 = H, R 3 = 2-MeOC 6 H 4 ), 7f (R 1 = R 2 = H, R 3 = 3,4-Cl 2 C 6 H 3 ), 7g (R 1 = R 2 = H, R 3 = 3-H 3 CC 6 H 4 ), 9a (R = 3,4-Cl 2 ), and Remdesivir respectively [ 115 ]. Scheme 2 Synthesis of 2,3-dithioindoles 9.…”
“…Firstly, Virus blocks recognition of Rig-1 and MDA5 of viral RNA, by masking their 50 ends through guanine N7 methyltransferase and 20-Omethyltransferase action 68 . In addition, www.minarjournal.com excess production of nucleocapsid protein and nsp5 that blocks Rig-1 by blocking the TRIM25 induced ubiquitination 69 .…”
Section: Sars Cov2 Impact On Interferon I and Iii Responsesmentioning
SARS-CoV-2 is a new beta coronavirus, similar to SARS-CoV-1, that emerged at the end of 2019 in the Hubei province of China. It is responsible for coronavirus disease 2019 (COVID-19), which was declared a pandemic by the World Health Organization on March 11, 2020. The ability to gain quick control of the pandemic has been hampered by a lack of detailed knowledge about SARS-CoV-2-host interactions, mainly in relation to viral biology and host immune response. The rapid clinical course seen in COVID-19 indicates that infection control in asymptomatic patients or patients with mild disease is probably due to the innate immune response, as, considering that SARS -CoV-2 is new to humans, an effective adaptive response would not be expected to occur until approximately 2---3 weeks after contact with the virus. Antiviral innate immunity has humoral components (complement and coagulation -fibrinolysis systems, soluble proteins that recognize glycans on cell surface, interferons, chemokines, and naturally occurring antibodies) and cellular components (natural killer cells and other innate lymphocytes). Failure of this system would pave the way for uncontrolled viral replication in the airways and the mounting of an adaptive immune response, potentially amplified by an inflammatory cascade. Severe COVID-19 appears to be due not only to viral infection but also to a dysregulated immune and inflammatory response. In this paper, the authors review the most recent publications on the immunobiology of SARS-CoV-2, virus interactions with target cells, and host immune responses, and highlight possible associations between deficient innate and acquired immune responses and disease progression and mortality. Immunotherapeutic strategies targeting both the virus and dysfunctional immune responses are also addressed.
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