Tanshinone IIA for COVID-19

(1) Background: The SARS-CoV-2 papain-like protease (PLpro) remains an underexplored antiviral target so far. The reduced efficacy of approved treatments against novel variants highlights the importance of developing new agents. This review aims to provide a comprehensive understanding of phytochemicals as inhibitors of PLpro, identify gaps, and propose novel insights for future reference. (2) Methods: A thorough literature search was conducted using Google Scholar, ScienceDirect, and PubMed. Out of 150 articles reviewed, 57 met inclusion criteria, focusing on SARS-CoV-2 PLpro inhibitors, excluding studies on other coronaviruses or solely herbal extracts. Data were presented class-wise, and phytochemicals were grouped into virtual, weak, modest, and potential inhibitors. (3) Results: Approximately 100 phytochemicals are reported in the literature as PLpro inhibitors. We classified them as virtual inhibitors (70), weak inhibitors (13), modest inhibitors (11), and potential inhibitors (6). Flavonoids, terpenoids, and their glycosides predominated. Notably, six phytochemicals, including schaftoside, tanshinones, hypericin, and methyl 3,4-dihydroxybenzoate, emerged as potent PLpro inhibitors with favorable selectivity indices and disease-mitigation potential; (4) Conclusions: PLpro stands as a promising therapeutic target against SARS-CoV-2. The phytochemicals reported in the literature possess valuable drug potential; however, certain experimental and clinical gaps need to be filled to meet the therapeutic needs.

AbstractDanshen, a prominent herb in traditional Chinese medicine (TCM), is known for its potential to enhance physiological functions such as blood circulation, immune response, and resolve blood stasis. Despite the effectiveness of COVID-19 vaccination efforts, some individuals still face severe complications post-infection, including pulmonary fibrosis, myocarditis arrhythmias and stroke. This study employs a network pharmacology and molecular docking approach to investigate the potential mechanisms underlying the therapeutic effects of candidate components and targets from Danshen in the treatment of complications in COVID-19. Candidate components and targets from Danshen were extracted from the TCMSP Database, while COVID-19-related targets were obtained from Genecards. Venn diagram analysis identified common targets. A Protein–Protein interaction (PPI) network and gene enrichment analysis elucidated potential therapeutic mechanisms. Molecular docking evaluated interactions between core targets and candidate components, followed by molecular dynamics simulations to assess stability. We identified 59 potential candidate components and 123 targets in Danshen for COVID-19 treatment. PPI analysis revealed 12 core targets, and gene enrichment analysis highlighted modulated pathways. Molecular docking showed favorable interactions, with molecular dynamics simulations indicating high stability of key complexes. Receiver operating characteristic (ROC) curves validated the docking protocol. Our study unveils candidate compounds, core targets, and molecular mechanisms of Danshen in COVID-19 treatment. These findings provide a scientific foundation for further research and potential development of therapeutic drugs.

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.