GRL-0617 for COVID-19
GRL-0617 has been reported as potentially beneficial for treatment of COVID-19. We have not reviewed these studies. See all other treatments.
Inhibitors of SARS-CoV-2 PLpro, Frontiers in Chemistry, doi:10.3389/fchem.2022.876212 ,
The emergence of SARS-CoV-2 causing the COVID-19 pandemic, has highlighted how a combination of urgency, collaboration and building on existing research can enable rapid vaccine development to fight disease outbreaks. However, even countries with high vaccination rates still see surges in case numbers and high numbers of hospitalized patients. The development of antiviral treatments hence remains a top priority in preventing hospitalization and death of COVID-19 patients, and eventually bringing an end to the SARS-CoV-2 pandemic. The SARS-CoV-2 proteome contains several essential enzymatic activities embedded within its non-structural proteins (nsps). We here focus on nsp3, that harbours an essential papain-like protease (PLpro) domain responsible for cleaving the viral polyprotein as part of viral processing. Moreover, nsp3/PLpro also cleaves ubiquitin and ISG15 modifications within the host cell, derailing innate immune responses. Small molecule inhibition of the PLpro protease domain significantly reduces viral loads in SARS-CoV-2 infection models, suggesting that PLpro is an excellent drug target for next generation antivirals. In this review we discuss the conserved structure and function of PLpro and the ongoing efforts to design small molecule PLpro inhibitors that exploit this knowledge. We first discuss the many drug repurposing attempts, concluding that it is unlikely that PLpro-targeting drugs already exist. We next discuss the wealth of structural information on SARS-CoV-2 PLpro inhibition, for which there are now ∼30 distinct crystal structures with small molecule inhibitors bound in a surprising number of distinct crystallographic settings. We focus on optimisation of an existing compound class, based on SARS-CoV PLpro inhibitor GRL-0617, and recapitulate how new GRL-0617 derivatives exploit different features of PLpro, to overcome some compound liabilities.
Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors, Bioorganic & Medicinal Chemistry, doi:10.1016/j.bmc.2020.115860 ,
Targeting SARS-CoV-2 Non-Structural Proteins, International Journal of Molecular Sciences, doi:10.3390/ijms241613002 ,
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an enveloped respiratory β coronavirus that causes coronavirus disease (COVID-19), leading to a deadly pandemic that has claimed millions of lives worldwide. Like other coronaviruses, the SARS-CoV-2 genome also codes for non-structural proteins (NSPs). These NSPs are found within open reading frame 1a (ORF1a) and open reading frame 1ab (ORF1ab) of the SARS-CoV-2 genome and encode NSP1 to NSP11 and NSP12 to NSP16, respectively. This study aimed to collect the available literature regarding NSP inhibitors. In addition, we searched the natural product database looking for similar structures. The results showed that similar structures could be tested as potential inhibitors of the NSPs.
COVID-19 signalome: Potential therapeutic interventions, Cellular Signalling, doi:10.1016/j.cellsig.2022.110559 ,
Polyphenols as alternative treatments of COVID-19, Computational and Structural Biotechnology Journal, doi:10.1016/j.csbj.2021.09.022 ,
Identifying Drug Candidates for COVID-19 with Large-Scale Drug Screening, International Journal of Molecular Sciences, doi:10.3390/ijms24054397 ,
Papain-like protease (PLpro) is critical to COVID-19 infection. Therefore, it is a significant target protein for drug development. We virtually screened a 26,193 compound library against the PLpro of SARS-CoV-2 and identified several drug candidates with convincing binding affinities. The three best compounds all had better estimated binding energy than those of the drug candidates proposed in previous studies. By analyzing the docking results for the drug candidates identified in this and previous studies, we demonstrate that the critical interactions between the compounds and PLpro proposed by the computational approaches are consistent with those proposed by the biological experiments. In addition, the predicted binding energies of the compounds in the dataset showed a similar trend as their IC50 values. The predicted ADME and drug-likeness properties also suggested that these identified compounds can be used for COVID-19 treatment.
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