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

被引:426
作者
Liu, SW
Xiao, GF
Chen, YB
He, YX
Niu, JK
Escalante, CR
Xiong, HB
Farmar, J
Debnath, AK
Tien, P
Jiang, SB
机构
[1] New York Blood Ctr, Lindsley F Kimball Res Inst, New York, NY 10021 USA
[2] Wuhan Univ, Modern Virol Res Ctr, Wuhan 430072, Peoples R China
[3] Mt Sinai Sch Med, New York, NY USA
关键词
D O I
10.1016/S0140-6736(04)15788-7
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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. CIPA 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.
引用
收藏
页码:938 / 947
页数:10
相关论文
共 50 条
  • [1] [Anonymous], 2004, SUMMARY PROBABLE SAR
  • [2] TRIMERIC SUBDOMAIN OF THE SIMIAN IMMUNODEFICIENCY VIRUS GLYCOPROTEIN
    BLACKLOW, SC
    LU, M
    KIM, P
    [J]. BIOCHEMISTRY, 1995, 34 (46) : 14955 - 14962
  • [3] The coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex
    Bosch, BJ
    van der Zee, R
    de Haan, CAM
    Rottier, PJM
    [J]. JOURNAL OF VIROLOGY, 2003, 77 (16) : 8801 - 8811
  • [4] Cavanagh D., 1995, CORONAVIRIDAE, P73, DOI DOI 10.1007/978-1-4899-1531-3_5
  • [5] Core structure of gp41 from the HIV envelope glycoprotein
    Chan, DC
    Fass, D
    Berger, JM
    Kim, PS
    [J]. CELL, 1997, 89 (02) : 263 - 273
  • [6] Evidence that a prominent cavity in the coiled coil of HIV type 1 gp41 is an attractive drug target
    Chan, DC
    Chutkowski, CT
    Kim, PS
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) : 15613 - 15617
  • [7] HIV entry and its inhibition
    Chan, DC
    Kim, PS
    [J]. CELL, 1998, 93 (05) : 681 - 684
  • [8] Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1
    Debnath, AK
    Radigan, L
    Jiang, SB
    [J]. JOURNAL OF MEDICINAL CHEMISTRY, 1999, 42 (17) : 3203 - 3209
  • [9] Identification of a novel coronavirus in patients with severe acute respiratory syndrome
    Drosten, C
    Günther, S
    Preiser, W
    van der Werf, S
    Brodt, HR
    Becker, S
    Rabenau, H
    Panning, M
    Kolesnikova, L
    Fouchier, RAM
    Berger, A
    Burguière, AM
    Cinatl, J
    Eickmann, M
    Escriou, N
    Grywna, K
    Kramme, S
    Manuguerra, JC
    Müller, S
    Rickerts, V
    Stürmer, M
    Vieth, S
    Klenk, HD
    Osterhaus, ADME
    Schmitz, H
    Doerr, HW
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 2003, 348 (20) : 1967 - 1976
  • [10] The hydrophobic pocket contributes to the structural stability of the N-terminal coiled coil of HIV gp41 but is not required for six-helix bundle formation
    Dwyer, JJ
    Hasan, A
    Wilson, KL
    White, JM
    Matthews, TJ
    Delmedico, MK
    [J]. BIOCHEMISTRY, 2003, 42 (17) : 4945 - 4953