As we all know, the SARS-CoV-1 virus caused the 2002-2004 SARS outbreak. Today, we will introduce a virus — SARS-CoV-2.  SARS-CoV-2 is related to the SARS-CoV-1 virus. SARS-CoV-2 belongs to the broad family of coronaviruses. It is a single-stranded RNA (+ssRNA) virus with a single linear RNA fragment. In particular, SARS-CoV-2 is airborne and spreads from person to person. Importantly, it can bind to human cells through angiotensin-converting enzyme 2 (ACE2). ACE2 is a membrane protein in human cells. And it regulates the renin-angiotensin system. SARS-CoV-2 has enough affinity for ACE2, so it can use them as a cell entry mechanism.

RAY1216 is an Orally Active SARS-CoV-2 Main Protease Slow-tight Inhibitor

RAY1216 is a SARS-CoV-2 main protease slow-tight inhibitor with a K_i value of 8.6 nM. On the one hand, it exhibits antiviral activity against SARS-CoV-2 wild-type progenitor and mutant strains. RAY1216 has an inhibitory effect against different SARS-CoV-2 variants with EC₅₀ values of 95 nM (WT), 130 nM (Alpha), 277 nM (Beta), 97 nM (Delta), 86 nM (Omicron BA.1) and 158 nM (Omicron BA.5), respectively. On the other hand, RAY1216 has a drug on-target residence time of 104 minutes.  Moreover, it can attach to the catalytic Cys145 via α-ketoamide warhead.

In vivo, RAY1216 (150-600 mg/kg/day; i.g.; 5 days) effectively prolongs the survival of SARS-CoV-2-infected mice. Besides, RAY1216 decreased significantly viral titers in the lungs compared with the infection-only group. Reduced virus-induced pathology. In addition, it shows a promising human pharmacokinetics profile.

In conclusion, RAY1216 is an orally active slow-tight inhibitor of the major protease of SARS-CoV-2. And it can be used in novel coronavirus research.

References:

[1] Cody B Jackson, et al. Epub 2021 Oct 5.

[2] Xiaoxin Chen, et al. BioRxiv 2023.03.09.531862.