Signal Transduction and Targeted Therapy has recently published a review article that reported the current expertise about how SARS-CoV-2 attaches on the surface of host cells through a variety of receptors, such as ACE2, neuropilin-1, AXL, and antibody-FcyR complexes. In the article, researchers illustrated how its spike (S) protein has a conformational transition from prefusion to postfusion with the help of proteases, such as furin, TMPRSS2, and cathepsins. Researchers also examine the current experimental studies and clinical trials of antibodies, peptides, or small-molecule compounds targeting host-pathogen interaction could potentially suppress viral attachment, reduce the exposure of fusion peptide to curtail membrane fusion, and block the formation of six-helix bundle (6-HB) fusion core.

There is one session in the article specifically talking about small-molecule compound-based antiviral therapies, including small molecules targeting S protein of SARS-CoV-2, TMPRSS2 inhibitors, and cathepsin B/L inhibitor.

Small molecules targeting S protein

In the article, the researchers concluded that the S protein of SARS-CoV-2 plays an important role in receptor recognition and virus-cell membrane fusion, and because of this, S protein is also an important target for antiviral therapy. It is found that a hydrophilic compound, Salvianolic acid isolated from traditional Chinese medicine, inhibited SAR-CoV-2 infection by blocking the formation of 6-HB core in authentic SARS-CoV-2 inhibition assays. Also, researchers quoted that, two novel drug-like compounds, DRI-C23041 and DRI-C91005, showed antiviral activity in obstructing the interaction between hACE2 and SARS-CoV-2 S protein. More, DRI-C23041 is also found to be inhibited the entry of SARS-CoV-2-S pseudo viral into ACE2-expressing cells.

TMPRSS2 inhibitors

In the article, the researchers commented that TMPRSS2 could be used as a target to prevent virus entry. It is found that Camostat mesylate, a clinically proven TMPRSS2 inhibitor, significantly inhibited SARS-CoV-2 pseudo viral entry into Calu-3 cells. In addition, camostat mesylate is found to be significantly reduced authentic SARS-CoV2 infection in Calu-3 cells and reduced SARS-CoV-2 pseudovirus infection in primary human lung cells by researchers. A randomized clinical trial (Phase IIa, ClinicalTrials.gov, NCT04321096) had been conducted to evaluate camostat mesylate as a treatment for SARS-CoV-2. In addition, double-blinded, randomized placebo-controlled trials (phase IV, ClinicalTrials.gov, NCT04338906) had been conducted on 334 COVID-19 patients. Moreover, the article also stated that bromhexine, a generic mucolytic targeting TMPRSS2, is currently being examined clinically for SARS-CoV-2 (ClinicalTrials.gov, NCT04273763, and NCT04340349). Also, researchers quoted that, MI-432 and MI-1900 are two prospective peptide mimetic inhibitors of TMPRSS2 and both demonstrated antiviral activity against SARS-CoV-2 infection in vitro.

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Cathepsin B/L inhibitors

In addition to TMPRSS2, the article mentioned that cellular cathepsins can prime viral S protein cleavage and benefit viral fusion, including cathepsin B and cathepsin L, which become active in the early and late endosome, respectively, and known activators for fusion.

  • Researchers quoted that, P9, which derived from mouse β-defensin-4, has broad-spectrum antiviral activity against multiple respiratory viruses by interfering with cathepsin L. It is found that the P9-optimized product, P9R, showed antiviral activity against SARS-CoV-2 in a plaque reduction assay. The eight-branched derivative, 8P9R, is found to demonstrate more potent antiviral activity and can inhibit both endocytic and surface pathways of SARS-CoV-2 mediated by TMPRSS2 by aggregating virus particles. In vivo, 8P9R alone, or in combination with other drugs (arbidol, chloroquine, and camostat), could significantly inhibit SARS-CoV-2 replication in hamsters.
  • E64-d, a broad cathepsin B/L inhibitor which has been examined in the article, showed inhibitory activity in a SARS-CoV-2 pseudovirus infection assay.
  • More, Teicoplanin, an antibiotic currently used for the treatment of Gram-positive bacterial infections, is found to have antiviral activity against SARS-CoV, MERS-CoV, and Ebola virus in vitro. It is found to be acting on the early step of the coronavirus viral life cycle by directly inhibiting the enzymatic activity of cathepsin L. Besides, researchers quoted that, Teicoplanin inhibited SARS-CoV-2 pseudovirus infection with a half-maximal inhibitory concentration (IC50) much lower than the commonly used dose of IC50 to inhibit Gram-positive bacteria. More investigation of Teicoplanin was encouraged for the treatment of COVID-19 disease in the article.


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The full article of Signal Transduction and Targeted Therapy is available here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8193598/pdf/41392_2021_Article_653.pdf


Zhang Q, Xiang R, Huo S, Zhou Y, Jiang S, Wang Q, Yu F. Molecular mechanism of interaction between SARS-CoV-2 and host cells and interventional therapy. Signal Transduct Target Ther. 2021 Jun 11;6(1):233. doi: 10.1038/s41392-021-00653-w. PMID: 34117216; PMCID: PMC8193598.

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