SARS-CoV-2 PL^pro (SARS-CoV-2 papain-like protease) is the largest of the SARS-CoV-2 non-structural proteins (212 kDa). Importantly, the amino acid sequence of SARS-CoV-2PL^pro is 98 % identical to related proteases from bat coronaviruses BANAL-52 and RaTG13, and 83 % identical to the related human coronavirus SARS-CoV-1. Particularly, The active sites of SARS-CoV-1 and SARS-CoV-2 PL^pro are almost identical. Moreover, SARS-CoV-2 PL^pro is essential for viral replication and is considered a valid target for antiviral drug development.

SARS-CoV-2 M^pro (SARS-CoV-2 main protease) is a class of highly conserved cysteine hydrolases in coronaviruses. While SARS-CoV-2 M^pro has capable of cleaving polyproteins at multiple sites to yield multiple functional proteins. Importantly, no homolog of ^pro has been identified in humans, so it is feasible to develop efficacious and specific M^pro inhibitors on human proteases.

LY1 is a selective and covalent inhibitor against SARS-CoV-2 PL^pro and M^pro.

LY1 binds to SARS-CoV-2 PL^pro and SARS-CoV-2 M^pro with K_d values of 1.5, 2.3 µM for M^pro C145A and PL^pro C111A, respectively. This inhibitor also shows significant inhibitory activity against M^pro and PL^pro with IC₅₀ values of 0.12, 0.99 µM, respectively. In SARS-CoV-2-infected Vero E6 cells, LY1 (2.5-15 μM) causes a dramatic reduction in the viral nucleoprotein (NP) levels with 5 μM. A 99.99% reduction in the viral RdRP RNA levels at 15 μM. LY1 shows no cytotoxic at 5-25 μM in SARS-CoV-2-infected Vero E6 cells. Moreover, in the 8-week toxicity study, LY1 (300 mg/kg, p.o., 4 weeks) shows no significant change in body weight and food consumption in rats.

In a word, LY1 is a potent, selective and covalent inhibitor against both SARS-CoV-2 PL^pro and SARS-CoV-2 M^pro. LY1 has the potential for research on COVID-19.

References:

[1] Ullrich S, et al. Chembiochem. 2022 Oct 6;23(19):e202200327.

[2] Hu Q, et al. MedComm (2020). 2022 Jul 14;3(3):e151.

[3] Yu W, et al. J Med Chem. 2022 Dec 22;65(24):16252-16267.