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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.
Lancet. 2004 Mar 20; 363(9413):938-47.Lct

Abstract

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 alpha-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.

Authors+Show Affiliations

Lindsley F Kimball Research Institute, New York Blood Center, New York, NY 10021, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

15043961

Citation

Liu, Shuwen, et al. "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." Lancet (London, England), vol. 363, no. 9413, 2004, pp. 938-47.
Liu S, Xiao G, Chen Y, et al. 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. Lancet. 2004;363(9413):938-47.
Liu, S., Xiao, G., Chen, Y., He, Y., Niu, J., Escalante, C. R., Xiong, H., Farmar, J., Debnath, A. K., Tien, P., & Jiang, S. (2004). 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. Lancet (London, England), 363(9413), 938-47.
Liu S, et al. 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. Lancet. 2004 Mar 20;363(9413):938-47. PubMed PMID: 15043961.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Liu,Shuwen, AU - Xiao,Gengfu, AU - Chen,Yibang, AU - He,Yuxian, AU - Niu,Jinkui, AU - Escalante,Carlos R, AU - Xiong,Huabao, AU - Farmar,James, AU - Debnath,Asim K, AU - Tien,Po, AU - Jiang,Shibo, PY - 2004/3/27/pubmed PY - 2004/4/28/medline PY - 2004/3/27/entrez SP - 938 EP - 47 JF - Lancet (London, England) JO - Lancet VL - 363 IS - 9413 N2 - 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 alpha-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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/15043961/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(04)15788-7 DB - PRIME DP - Unbound Medicine ER -