Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors
| Autor: | James Farmar, Jinkui Niu, Huabao Xiong, Gengfu Xiao, Yuxian He, Po Tien, Shibo Jiang, Carlos R. Escalante, Asim K. Debnath, Yibang Chen, Shuwen Liu |
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| Rok vydání: | 2004 |
| Předmět: |
Circular dichroism
Anti-HIV Agents Protein Conformation viruses Peptide Biology Chemical Fractionation medicine.disease_cause Gp41 Severe Acute Respiratory Syndrome Membrane Fusion Article Viral Envelope Proteins Sequence Homology Nucleic Acid medicine Humans Polyacrylamide gel electrophoresis Cells Cultured Chromatography High Pressure Liquid Coronavirus chemistry.chemical_classification Membrane Glycoproteins Circular Dichroism General Medicine Surface Plasmon Resonance Transmembrane protein HIV Envelope Protein gp41 Heptad repeat chemistry Biochemistry Severe acute respiratory syndrome-related coronavirus Spike Glycoprotein Coronavirus Biophysics Electrophoresis Polyacrylamide Gel Glycoprotein Oligopeptides Viral Fusion Proteins |
| Zdroj: | Lancet (London, England) |
| ISSN: | 1474-547X |
| Popis: | Summary Background Studies on the fusion-inhibitory peptides derived from the heptad repeat 1 and 2 (HR1 and HR2) regions of the HIV-1 envelope glycoprotein gp41 provided crucial information on the viral fusogenic mechanism. We used a similar approach to study the fusogenic mechanism of severe-acute-respiratory-syndrome-associated coronavirus (SARS-CoV). Methods We tested the inhibitory activity against infection of two sets of peptides corresponding to sequences of SARS-CoV spike protein HR1 and HR2 regions and investigated the interactions between the HR1 and HR2 peptides by surface plasmon resonance, sedimentation equilibration analysis, circular dichroism, native polyacrylamide-gel electrophoresis, size exclusion high-performance liquid chromatography, and computer-aided homology modelling and molecule docking analysis. Findings One peptide, CP-1, derived from the HR2 region, inhibited SARS-CoV infection in the micromolar range. CP-1 bound with high affinity to a peptide from the HR1 region, NP-1. CP-1 alone had low -helicity and self-associated to form a trimer in phosphate buffer (pH 7·2). CP-1 and NP-1 mixed in equimolar concentrations formed a six-helix bundle, similar to the fusogenic core structure of HIV-1 gp41. Interpretation After binding to the target cell, the transmembrane spike protein might change conformation by association between the HR1 and HR2 regions to form an oligomeric structure, leading to fusion between the viral and target-cell membranes. At the prefusion intermediate state, CP-1 could bind to the HR1 region and interfere with the conformational changes, resulting in inhibition of SARS-CoV fusion with the target cells. CP-1 might be modifiable to increase its anti-SARS-CoV activity and could be further developed as an antiviral agent for treatment or prophylaxis of SARS-CoV infection. |
| Databáze: | OpenAIRE |
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