S-217622, 3C-like protease inhibitor clinical candidate for COVID-19

The pathogen causing New Coronavirus pneumonia is a beta genus coronavirus called SARS-CoV-2, which is an RNA virus. After entering cells through the human ACE2 receptor, SARS-CoV-2 translates and expresses the polyprotein pp1a/pp1ab, which is then hydrolyzed by Mpro or 3CLpro or nsp5 to release various nonstructural proteins that are important for virus replication, thus inhibiting the activity of 3CL protease and blocking virus replication.

In order to obtain non-covalent 3CL protease inhibitors as clinical candidates quickly, Shionogi performed docking-based virtual screening and biological screening of its in-house compound library to obtain hit compounds (Hits), followed by structure optimization of Hits using a structure-based drug design (SBDD) strategy.

The hit compound 1 exhibited strong enzyme inhibition and superior PK properties (good oral bioavailability), thus the hit compound 1 was selected for optimization studies. By resolving the eutectic structure of compound 1 and 3CL protease, analyzing their binding poses and interaction modes, the structure-based drug design (SBDD) strategy was used to optimize the P1' fragment and P1 fragment of compound 1, respectively, resulting in the clinical candidate S-217622.

S-217622 showed promising activity (IC50 = 0.013 μM, EC50 = 0.37 μM) and oral bioavailability (stable metabolism, high oral absorption, low clearance). Also, it showed better inhibition against SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-229E and other beta genus coronaviruses. The antiviral effect of S-217622 against SARS-CoV-2 Gamma strain was evaluated in mice. S-217622 treatment was given 12 hours after mice were infected with SARS-CoV-2 Gamma strain, and the results showed that S-217622 dose-dependently reduced the virus titer in the lungs of mice. S-217622 is currently undergoing clinical trial studies and is expected to be the first non-covalent non-peptide oral 3CL protease inhibitor for COVID-19 treatment.

Huateng pharma, as a leading CDMO in China, provides Ensitrelvir (S-217622) intermediates with lab to commercial scale.