ABSTRACT
New variants of the severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) emerged and spread rapidly all over the world, which strongly supports the need for pharmacological options to complement vaccine strategies. Main protease (Mpro or 3CLpro) is a critical enzyme in the life cycle of SARS-CoV-2 and appears to be highly conserved among different genera of coronaviruses, making it an ideal target for the development of drugs with broad-spectrum property. PF-07304814 developed by Pfizer is an intravenously administered inhibitor targeting SARS-CoV-2 Mpro. Here we showed that PF-07304814 displays broad-spectrum inhibitory activity against Mpros from multiple coronaviruses. Crystal structures of Mpros of SARS-CoV-2, SARS-CoV, MERS-CoV, and HCoV-NL63 bound to the inhibitor PF-07304814 revealed a conserved ligand-binding site, providing new insights into the mechanism of inhibition of viral replication. A detailed analysis of these crystal structures complemented by comprehensive comparison defined the key structural determinants essential for inhibition and illustrated the binding mode of action of Mpros from different coronaviruses. In view of the importance of Mpro for the medications of SARS-CoV-2 infection, insights derived from the present study should accelerate the design of pan-coronaviral main protease inhibitors that are safer and more effective.
Subject(s)
Coronavirus 3C Proteases , Coronavirus Protease Inhibitors , Indoles , Leucine , Pyrrolidinones , SARS-CoV-2 , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Coronavirus Protease Inhibitors/chemistry , Coronavirus Protease Inhibitors/pharmacology , Drug Design , Humans , Indoles/chemistry , Indoles/pharmacology , Leucine/chemistry , Leucine/pharmacology , Ligands , Protein Binding , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/enzymologyABSTRACT
Rupintrivir targets the 3C cysteine proteases of the picornaviridae family, which includes rhinoviruses and enteroviruses that cause a range of human diseases. Despite being a pan-3C protease inhibitor, rupintrivir activity is extremely weak against the homologous 3C-like protease of SARS-CoV-2. In this study, the crystal structures of rupintrivir were determined bound to enterovirus 68 (EV68) 3C protease and the 3C-like main protease (Mpro) from SARS-CoV-2. While the EV68 3C protease-rupintrivir structure was similar to previously determined complexes with other picornavirus 3C proteases, rupintrivir bound in a unique conformation to the active site of SARS-CoV-2 Mpro splitting the catalytic cysteine and histidine residues. This bifurcation of the catalytic dyad may provide a novel approach for inhibiting cysteine proteases.
Subject(s)
Antiviral Agents/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Isoxazoles/metabolism , Phenylalanine/analogs & derivatives , Pyrrolidinones/metabolism , SARS-CoV-2/enzymology , Valine/analogs & derivatives , Antiviral Agents/chemistry , Catalytic Domain , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus 3C Proteases/chemistry , Crystallography, X-Ray , Cysteine Proteinase Inhibitors/chemistry , Enterovirus D, Human/enzymology , Hydrogen Bonding , Isoxazoles/chemistry , Phenylalanine/chemistry , Phenylalanine/metabolism , Protein Binding , Pyrrolidinones/chemistry , Static Electricity , Valine/chemistry , Valine/metabolismABSTRACT
The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.
Subject(s)
Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Indoles/chemistry , Indoles/pharmacology , Leucine/chemistry , Leucine/pharmacology , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Pyrrolidinones/chemistry , Pyrrolidinones/pharmacology , Binding Sites , Computer Simulation , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Databases, Protein , Diarylquinolines/chemistry , Diarylquinolines/pharmacology , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitrobenzenes/chemistry , Nitrobenzenes/pharmacology , Nitrophenols/chemistry , Nitrophenols/pharmacology , Organophosphorus Compounds/chemistry , Organophosphorus Compounds/pharmacology , Piperazines/chemistry , Piperazines/pharmacology , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , COVID-19 Drug TreatmentABSTRACT
With the current global outbreak of novel coronaviruses, the fabrication of decomposable wet wipe with sufficient wet strength to meet daily use is promising but still challenging, especially when renewable cellulose was employed. In this work, a decomposable cellulose-based wet wipe substrate is demonstrated by introducing a synthetic N-vinyl pyrrolidone-glycidyl methacrylate (NVP-GMA) adhesive on the cellulose surface. Experimental results reveal that the NVP-GMA adhesive not only significantly facilitates the chemical bonding between cellulose fibers in the wet state, but also increase the surface wettability and water retention. The as-fabricated cellulose-based wet wipe substrate displays a superb water retention capacity of 1.9 times, an excellent water absorption capacity (completely wetted with 0° water contact angle), and a perfect wet tensile index of 3.32 N.m.g-1. It is far better than state-of-the-art wet toilet wipe on the market (non-woven). The prepared renewable and degradable cellulose-based substrate with excellent mechanical strength has potential application prospects in diverse commercially available products such as sanitary and medical wet wipes.