Discovery of novel non-peptidic and non-covalent small-molecule 3CLpro inhibitors as potential candidate for COVID-19 treatment
Zhidong Jiang, Bo Feng, Yumin Zhang, Tianqing Nie, Hong Liu, Jia Li, Haixia Su, Leike Zhang, Yi Zang, Yu Zhou
Abstract
The global coronavirus disease 2019 (COVID-19) pandemic, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has brought a profound impact on humanity. SARS-CoV-2 enters host cells through the interaction of its spike glycoprotein with angiotensin-converting enzyme 2 (ACE2) of the host and releases its viral RNA genome. 1 The genome is further translated into two polyproteins, PP1a and PP1ab, that contain 16 non-structural proteins, in which the non-structural protein 5 (also called as 3C-Like protease, 3CL pro ) plays a vital role in the life cycle of the virus. 2 As a consequence, multiple peptide-like covalent 3CL pro inhibitors have been successively reported to show good 3CL pro inhibitory potencies and antiviral activities. 3 , 4 However, the defects of peptidomimetic inhibitors about low membrane permeability and metabolic stability are obvious, in which the approved drug paxlovid (PF-07321332) from Pfizer must be co-administrated with ritonavir as a pharmacokinetic booster. 3 Non-peptidic small molecule inhibitors may have more advantages in metabolic properties and are gradually attracting attention. 5 , 6 , 7 Our research attempted to discover a novel non-peptidic and non-covalent small molecule 3CL pro inhibitor so as to give better drug-like properties and good antiviral activities.