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

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 Ki 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.



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

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