A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors

Abstract

Graphical abstract

A Patent Review on SARS Coronavirus Main Protease (3CLpro) Inhibitors

“…Indeed, Pfizer's PF‐00835231 ( 6 b ), first described in WO 2005/113580, was originally designed to inhibit SARS‐CoV 3CL pro (IC 50 4 nM) [18] and was later shown to be a potent inhibitor of SARS‐CoV‐2 3CL pro (IC 50 8 nM). [45] …”

“… [50] Compound 5 c was later reported to inhibit SARS‐CoV‐2 3CL pro with an IC 50 of 286 nM. [45] In contrast, 5 d was reported to be a weak SARS‐CoV 3CL pro inhibitor (IC 50 85 μM), [51] suggesting that a P2 phenylalanine should be avoided in the design of new SARS‐CoV 3CL pro inhibitors. Compounds 5 e and 5 f , known as TG‐0205486 and TG‐0204998 respectively, were reported with K i s of 99 and 38 nM respectively.…”

“…A literature search revealed PF‐00835231 ( 6 b ; Figure 6 ) as the lead candidate with a very potent IC 50 of 4 nM against SARS‐CoV 3CL pro and a SARS‐CoV EC 50 of 4.8 μM in a SARS‐CoV infection cellular assay while a recent paper reported an IC 50 of 8 nM against SARS‐CoV‐2 3CL pro . [ 18 , 45 ] This strongly suggests that inhibitors designed to inhibit SARS‐CoV 3CL pro can be repurposed for SARS‐CoV‐2 3CL pro as both proteases share 96 % sequence identity. [ 12 , 17 ] The phosphate prodrug of PF‐0835231 entered phase 1 clinical trials in September 2020 to evaluate safety and pharmacokinetics in hospitalised COVID‐19 patients (ClinicalTrials.gov identifier: NCT04535167).…”

“… [61] Interestingly, 14 b /GC373 was shown to be much more active against SARS‐CoV‐2 3CL pro , exhibiting an IC 50 of 0.042 μM in a recent paper. [45] Similarly, 14 c /GC376 was also shown to be much more active against SARS‐CoV‐2 3CL pro , exhibiting IC 50 s ranging between 0.03 to 0.62 μM. [ 45 , 62 , 63 ] We opine ketoamide peptidomimetics 14 d and 14 f can potentially be further developed as SARS‐CoV‐2 3CL pro antivirals because ketoamide peptidomimetic protease inhibitors such as Boceprevir and Telaprevir have been approved for treating hepatitis C virus infections.…”

“…Indeed, Pfizer's PF-00835231 (6 b), first described in WO 2005/113580, was originally designed to inhibit SARS-CoV 3CL pro (IC 50 4 nM) [18] and was later shown to be a potent inhibitor of SARS-CoV-2 3CL pro (IC 50 8 nM). [45] To our best knowledge, the earliest patent application describing SARS-CoV 3CL pro inhibitors was filed by Pfizer in 2004 (WO 2004/093860; Table 1) [20] involving 3-residue peptidomimetics bearing a P1 glutamine or lactam glutamine mimic with a C-terminal electrophilic α,β-unsaturated ester warhead (Figure 1). Some inhibitors had their P3 amino acid residue substituted by a 2-pyridone moiety (1 b), presumably to improve their pharmacokinetic properties.…”