By October 2021, the COVID-19 pandemic had caused over five million deaths from 245 million total cases. While multiple vaccines are available as prophylactic measures, antiviral drugs for active case treatment are just arriving.
We initiated a SARS-CoV2 drug discovery project seeking to produce a lead for new antiviral. We chose target-based strategy and implement high throughput screening (HTS) focusing on four essential viral proteins, the main protease (Mpro), the papain-like protease (PLpro), the RNA-dependent RNA polymerase (RdRP) and the nidoviral RNA uridylate‐specific endoribonuclease (NendoU). While for some of these targets screening is still ongoing, we already found promising hits using our commercially sourced, in-house ~120k highly diverse small molecule library. A few hits have been followed up under a structure-guided medicinal chemistry optimization and proceeded to lead generation stage.
One series from Mpro screening has been intensively explored, leading to over 50 analogs with sub-100 nM potency against the enzyme. The current best compound NZ-804 showed an enzymatic IC50 of 8.9 nM, and cellular EC50 of 15 nM against the viral infection on the HeLa-ACE2 cells. NZ-804 also displayed high potency and low cytotoxicity on the polarized human upper airway epithelium monolayer disease model, outperforming remdesivir by as much as three-fold in terms of potency. NZ-804 demonstrated oral bioavailability during mouse pharmacokinetic studies and was well-tolerated by mice when dosing up to 50 mg/kg. More preclinical studies are under way for NZ-804.
Figure: Experiment procedure of target-based drug development taking Mpro as an example