Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the COVID-19 pandemic. Although different small-molecule therapeutics have been approved by the Food and Drug Administration of the U.S (FDA) for COVID-19 treatment, such as remdesivir, molnupiravir, and the viral main protease inhibitor, paxlovid. However, due to the rapid emergence of resistant virus variants, there is an urgent need to develop new therapeutic modalities. In addition, many studies have focused on targeting SARS-CoV-2 with small molecule inhibitors which block viral proteases and polymerases, including RNA-dependent RNA polymerase (RdRp), the main protease (Mpro or 3CLpro), and the papain-like protease (PLpro). In addition, RdRp and 3CLpro inhibitors have acquired for major progress. Therefore, many drugs are either FDA-approved or in clinical investigation. Hence, we will introduce a SARS-CoV-2 PLpro inhibitor-SIMR3030.

SIMR3030 is a potent SARS-CoV-2 PLpro inhibitor with an IC50 value of 0.0399 µg/mL.

SIMR3030 shows deubiquitinating activity and exhibits inhibition of SARS-CoV-2 specific gene expression (ORF1b and Spike) in infected host cells. Also, SIMR3030 possesses virucidal activity. In addition, SIMR3030 shows good antiviral activity in vivo and in vitro experiments.

In vitro, SIMR3030 (0-100 µg/mL) shows antiviral activity with IC50 values of 12.1, 6.206 μg/mL for SARS-CoV-2 and MERS-CoV, respectively. Moreover, SIMR3030 (20 µg/mL; 1, 6, 12 h) decreases SARS-CoV spike, ORF1b, IFN-α, IL-6 mRNA expression levels in Caco-2 cells. Furthermore, SIMR3030 shows good microsomal stability in liver microsomes.

In vivo, SIMR3030 (25, 50, 100 mg/kg; I.p.; daily for 14 days) maintains a high in vivo safety profile at different concentrations in experimental mice model.

All in all, SIMR3030 is a promising SARS-CoV-2 PLpro inhibitor for COVID-19 research.


[1] Hersi F, et al. Eur J Med Chem. 2023 Jun 5;254:115380.