Abstract
First identified in The Netherlands in 2004, human coronavirus NL63 (HCoV-NL63) was found to cause worldwide infections. Patients infected by HCoV-NL63 are typically young children with upper and lower respiratory tract infection, presenting with symptoms including croup, bronchiolitis, and pneumonia. Unfortunately, there are currently no effective antiviral therapy to contain HCoV-NL63 infection. CoV genomes encode an integral viral component, main protease (Mpro), which is essential for viral replication through proteolytic processing of RNA replicase machinery. Due to the sequence and structural conservation among all CoVs, Mpro has been recognized as an attractive molecular target for rational anti-CoV drug design. Here we present the crystal structure of HCoV-NL63 Mpro in complex with a Michael acceptor inhibitor N3. Structural analysis, consistent with biochemical inhibition results, reveals the molecular mechanism of enzyme inhibition at the highly conservative substrate-recognition pocket. We show such molecular target remains unchanged across 30 clinical isolates of HCoV-NL63 strains. Through comparative study with Mpros from other human CoVs (including the deadly SARS-CoV and MERS-CoV) and their related zoonotic CoVs, our structure of HCoV-NL63 Mpro provides critical insight into rational development of wide spectrum antiviral therapeutics to treat infections caused by human CoVs.
Highlights
Reservoir[20,21,22]
We have demonstrated that main protease (Mpro) is a conserved drug target throughout the subfamily Coronavirinae, which is suitable for designing wide-spectrum inhibitors[48,49]
These two polypeptides are cotranslationally cleaved into mature nonstructural proteins (Nsps) through two proteases encoded in the 5′ region of open reading frame 1 (ORF1): papain-like protease (PLP) and 3C-like protease (3CL or Nsp5)50,51. 3CL protease is more commonly known as Mpro because of its dominant role in the posttranslational processing of the replicase polyprotein
Summary
Reservoir[20,21,22]. While dromedary camels are suspected to be either reservoir or vector for MERS, as genomic sequence of isolated dromedary MERS-CoV was found identical to that of human MERS-CoV23–25. The Mpros from different human and animal CoVs are known to share significant homology in both primary amino acid sequence and 3D architecture, providing a strong structural basis for designing wide-spectrum anti-CoV inhibitors[48,49,52,53,54,55]. They employ a similar substrate-binding pocket, usually with a requirement for glutamine at P1 position and a preference for leucine/methionine at P2 position. Through comparison with Mpros from other CoVs, we provide structural insight into rational drug design at a conserved target across pathological human coronaviruses and their related zoonotic counterparts
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