Fusion core structure of the severe acute respiratory syndrome coronavirus (SARS-CoV): in search of potent SARS-CoV entry inhibitors.
Severe acute respiratory coronavirus (SARS-CoV) spike (S) glycoprotein fusion core consists of a six-helix bundle with the three C-terminal heptad repeat (HR2) helices packed against a central coiled-coil of the other three N-terminal heptad repeat (HR1) helices. Each of the three peripheral HR2 helices shows prominent contacts with the hydrophobic surface of the central HR1 coiled-coil. The concerted protein-protein interactions among the HR helices are responsible for the fusion event that leads to the release of the SARS-CoV nucleocapsid into the target host-cell. In this investigation, we applied recombinant protein and synthetic peptide-based biophysical assays to characterize the biological activities of the HR helices. In a parallel experiment, we employed a HIV-luc/SARS pseudotyped virus entry inhibition assay to screen for potent inhibitory activities on HR peptides derived from the SARS-CoV S protein HR regions and a series of other small-molecule drugs. Three HR peptides and five small-molecule drugs were identified as potential inhibitors. ADS-J1, which has been used to interfere with the fusogenesis of HIV-1 onto CD4+ cells, demonstrated the highest HIV-luc/SARS pseudotyped virus-entry inhibition activity among the other small-molecule drugs. Molecular modeling analysis suggested that ADS-J1 may bind to the deep pocket of the hydrophobic groove on the surface of the central coiled-coil of SARS-CoV S HR protein and prevent the entrance of the SARS-CoV into the host cells.
Chu
Ling-Hon Matthew
LH
Molecular Biotechnology Program, The Chinese University of Hong Kong, Hong Kong, China.
Chan
Siu-Hong
SH
Tsai
Sau-Na
SN
Wang
Yi
Y
Cheng
Christopher Hon-Ki
CH
Wong
Kam-Bo
KB
Waye
Mary Miu-Yee
MM
Ngai
Sai-Ming
SM
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D019295:Computational Biology; D015497:HIV-1 / Q000378:metabolism; D007834:Lasers; D008156:Luciferases / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D045473:Severe acute respiratory syndrome-related coronavirus / Q000737:chemistry*; D012542:Scattering, Radiation; D013816:Thermodynamics; D014760:Viral Fusion Proteins / Q000737:chemistry*; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents; D010455:Peptides; D011994:Recombinant Proteins; D014760:Viral Fusion Proteins; D008156:Luciferases