https://doi.org/10.1016/j.apsb.2025.09.026
This new article publication from Acta Pharmaceutica Sinica B, discusses the discovery of SARS-CoV-2 PLpro inhibitors and RIPK1 inhibitors with synergistic antiviral efficacy in a mouse COVID-19 model.
SARS-CoV-2 continues to propagate globally, posing non-negligible risks of severe COVID-19. Although several clinical antivirals and immunosuppressants offer crucial protection, there is a persistent need for additional therapeutic options to counter emerging viral variants and drug resistances. New strategies focusing on host targets, or simultaneously suppressing viral replication and inflammation, particularly require rigorous validation. Compared to established antiviral targets, PLpro presents an alternative actionable vulnerability in SARS-CoV-2 infection. Meanwhile, RIPK1 was pinpointed to enhance both viral replication and the resulting cytokine storm in host cells. However, inhibitors targeting PLpro or RIPK1 require further optimization for preclinical studies, and their combined efficacy in vivo has yet to be explored. The authors of this article report the discoveries of potent and selective PLpro inhibitors and RIPK1 inhibitors through high-throughput approaches. The lead compounds, SHY1643 and QY1892, demonstrated synergistic and robust effects in reducing the viral loads and cytokine release syndromes in SARS-CoV-2-infected mice. These findings establish a proof-of-concept combination therapy strategy for treating severe COVID-19, and provide promising leads for the clinical drug development.
Keywords: SARS-CoV-2, COVID-19, PLpro, RIPK1, Infective diseases, Cytokine storms, Small molecule inhibitors, Combination therapy
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525006276-ga1_lrg.jpg
High-throughput approaches-driven discovery of inhibitors, SHY1643 and QY1892, offers a promising combinational therapy for severe COVID-19 by synergistically targeting viral PLpro and host RIPK1.
