Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in millions of deaths and threatens public health and safety. Despite the rapid global spread of COVID-19 vaccines, effective oral antiviral drugs are urgently needed. Here, we describe the discovery of S-217622, the first oral non-covalent, non-peptidic SARS-CoV-2 3CL protease inhibitor clinical candidate. S-217622 was discovered via virtual screening followed by biological screening of an in-house compound library, and optimization of the hit compound using a structure-based drug-design strategy. S-217622 exhibited antiviral activity in vitro against current outbreaking SARS-CoV-2 variants and showed favorable pharmacokinetic profiles in vivo for once-daily oral dosing. Furthermore, S-217622 dose-dependently inhibited intrapulmonary replication of SARS-CoV-2 in mice, indicating that this novel non-covalent inhibitor could be a potential oral agent for treating COVID-19.
Competing Interest Statement
Y.U., S.U., K.N., H.N., Y.Y., S.Y., Y.M., Y.T., K.K., T.S., K.K., A.N., S.K., T.S., S.T., K.U., T.M., S.A., A.S., T.S., T.K., and Y.T. are employees of SHIONOGI & Co., Ltd. S.U., K.N., H.N., Y.M., Y.T., K.K., T.S., K.K., S.K., TS, S.T., K.U., T.S., and T.K. are shareholders in SHIONOGI & Co., Ltd. M.S., Y.O., and H.S. are financially supported by the joint research fund from SHIONOGI & Co., Ltd.
Abbreviations
- CDI
- N,N’-carbonyldiimidazole
- DBU
- 1,8-diazabicyclo[5.4.0]-7-undecene
- DMA
- N,N-dimethylacetamide
- DMEM
- dulbecco’s modified eagle medium
- DMSO
- dimethyl sulfoxide
- DTT
- 1,4-dithiothreitol
- ESI
- electrospray ionization
- EtOAc
- ethyl acetate
- HATU
- 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
- LCMS
- liquid chromatography mass spectrometry
- LHMDS
- lithium bis(trimethylsilyl)amide
- HRMS
- high resolution mass spectrometry
- MeCN
- acetonitrile
- TFA
- trifluoroacetic acid
- THF
- tetrahydrofuran.