Design of Wide-Spectrum Inhibitors Targeting Coronavirus Main Proteases

Abstract

The genus Coronavirus contains about 25 species of coronaviruses (CoVs), which are important pathogens causing highly prevalent diseases and often severe or fatal in humans and animals. No licensed specific drugs are available to prevent their infection. Different host receptors for cellular entry, poorly conserved structural proteins (antigens), and the high mutation and recombination rates of CoVs pose a significant problem in the development of wide-spectrum anti-CoV drugs and vaccines. CoV main proteases (Mpros), which are key enzymes in viral gene expression and replication, were revealed to share a highly conservative substrate-recognition pocket by comparison of four crystal structures and a homology model representing all three genetic clusters of the genus Coronavirus. This conclusion was further supported by enzyme activity assays. Mechanism-based irreversible inhibitors were designed, based on this conserved structural region, and a uniform inhibition mechanism was elucidated from the structures of Mpro-inhibitor complexes from severe acute respiratory syndrome-CoV and porcine transmissible gastroenteritis virus. A structure-assisted optimization program has yielded compounds with fast in vitro inactivation of multiple CoV Mpros, potent antiviral activity, and extremely low cellular toxicity in cell-based assays. Further modification could rapidly lead to the discovery of a single agent with clinical potential against existing and possible future emerging CoV-related diseases.

The newly emerged SARS-Like coronavirus HCoV-EMC also has an “Achilles’ heel”: current effective inhibitor targeting a 3C-like protease

“…pro (Yang et al, 2005). To be consistent with that the high similarities between the key residues of CoV 3CL pro s for substrate recognition, we found that N3 can effectively inhibit the proteolytic activity of HCoV-EMC 3CL pro with an IC 50 of 0.28 ± 0.02 μmol/L (Fig.…”

“…Since 3CL pro is unique in the virus but not found in the host cell, this protein is a prominent target for the development antivirals against CoV infections (Yang et al, 2005), and a number of inhibitors have been discovered that prohibit the infection of CoV through their action on 3CL pro (Yang et al, 2005).…”

Structures of Two Coronavirus Main Proteases: Implications for Substrate Binding and Antiviral Drug Design

“…Here, we also present the cocrystal structure of IBV M pro in complex with N3, a wide-spectrum inhibitor that we designed previously to target CoV M pro s (34). We further demonstrate its rapid in vitro inactivation against the viral protease and potent antiviral activity toward IBV in chicken embryos.…”

How Prepared Are We to Control Severe Acute Respiratory Syndrome in Future

“…It was reported to be 10 or 100 times more potent inhibitor of SARS-CoV than IFN-∝ and IFN-β, respectively (He et al, 2004) Chloroquine A clinically approved drug for malaria was effective with an IC50 in lower µM range (Keyaerts et al, 2004). In addition to its effect through elevation of endosomal pH, chloroquine seems to interfere with terminal glycosylation of ACE2, the the receptor for SARS-CoV (Vincent et al, 2005 (Li et al, 2005a;Wu and Huang, 2005;Zhao and Qin, 2005;Tang and Li, 2008) Homology modeling also formed a basis for designing mechanism-based irreversible inhibitors of 3CLpro with an activity of wide spectrum across coronaviruses (Yang et al, 2005a). Besides, several groups have identified a number of inhibitors of 3CLpro using a variety of approaches.…”