Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides: Implications for the viral fusion mechanism

被引:129
作者
Judice, JK [1 ]
Tom, JYK [1 ]
Huang, W [1 ]
Wrin, T [1 ]
Vennari, J [1 ]
Petropoulos, CJ [1 ]
McDowell, RS [1 ]
机构
[1] GENENTECH INC,RES VIROL LAB,DEPT PROC SCI,S SAN FRANCISCO,CA 94080
关键词
D O I
10.1073/pnas.94.25.13426
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Linear peptides derived from the membrane proximal region of the gp41 ectodomain are effective inhibitors of HIV type I (HIV-1)-mediated fusion events. These inhibitory peptides lack structure in solution, rendering mechanistic interpretation of their activity difficult. Using structurally constrained analogs of these molecules, we demonstrate that the peptides inhibit infectivity by adopting a helical conformation. Moreover, we show that a specific face of the helix must be exposed to block viral infectivity. Recent crystal structures show that the region of gp41 corresponding to the inhibitory peptides is helical and uses the analogous face to pack against a groove formed by an N-terminal coiled-coil trimer. Our results provide a direct link between the inhibition of HIV-1 infectivity by these peptides and the x-ray structures, and suggest that the conformation of gp41 observed by crystallography represents the fusogenic state. Other agents that block HIV-1 infectivity by binding to this groove may hold promise for the treatment of AIDS.
引用
收藏
页码:13426 / 13430
页数:5
相关论文
共 22 条
[1]   STRUCTURE OF INFLUENZA HEMAGGLUTININ AT THE PH OF MEMBRANE-FUSION [J].
BULLOUGH, PA ;
HUGHSON, FM ;
SKEHEL, JJ ;
WILEY, DC .
NATURE, 1994, 371 (6492) :37-43
[2]   A SPRING-LOADED MECHANISM FOR THE CONFORMATIONAL CHANGE OF INFLUENZA HEMAGGLUTININ [J].
CARR, CM ;
KIM, PS .
CELL, 1993, 73 (04) :823-832
[3]   Core structure of gp41 from the HIV envelope glycoprotein [J].
Chan, DC ;
Fass, D ;
Berger, JM ;
Kim, PS .
CELL, 1997, 89 (02) :263-273
[4]   Chemokines and HIV-1 second receptors - Confluence of two fields generates optimism in AIDS research [J].
DSouza, MP ;
Harden, VA .
NATURE MEDICINE, 1996, 2 (12) :1293-1300
[5]   SPECTROSCOPIC DETERMINATION OF TRYPTOPHAN AND TYROSINE IN PROTEINS [J].
EDELHOCH, H .
BIOCHEMISTRY, 1967, 6 (07) :1948-&
[6]   SOLID-PHASE PEPTIDE-SYNTHESIS UTILIZING 9-FLUORENYLMETHOXYCARBONYL AMINO-ACIDS [J].
FIELDS, GB ;
NOBLE, RL .
INTERNATIONAL JOURNAL OF PEPTIDE AND PROTEIN RESEARCH, 1990, 35 (03) :161-214
[7]   THE ROLE OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 ENVELOPE GLYCOPROTEINS IN VIRUS-INFECTION [J].
FREED, EO ;
MARTIN, MA .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (41) :23883-23886
[8]   A GENERAL-MODEL FOR THE TRANSMEMBRANE PROTEINS OF HIV AND OTHER RETROVIRUSES [J].
GALLAHER, WR ;
BALL, JM ;
GARRY, RF ;
GRIFFIN, MC ;
MONTELARO, RC .
AIDS RESEARCH AND HUMAN RETROVIRUSES, 1989, 5 (04) :431-440
[9]   Molecular cloning and analysis of functional envelope genes from human immunodeficiency virus type 1 sequence subtypes A through G [J].
Gao, F ;
Morrison, SG ;
Robertson, DL ;
Thornton, CL ;
Craig, S ;
Karlsson, G ;
Sodroski, J ;
Morgado, M ;
GalvaoCastro, B ;
vonBriesen, H ;
Beddows, S ;
Weber, J ;
Sharp, PM ;
Shaw, GM ;
Hahn, BH ;
Osmanov, S ;
Heyward, WL ;
Esparza, J ;
vandePerre, P ;
Karita, E ;
Sempala, S ;
Tugume, B ;
Biryahwaho, B ;
Wasi, C ;
RubsamenWaigmann, H ;
Holmes, H ;
Newberry, A ;
Ranjbar, S ;
Tomlinson, P ;
Bradac, J ;
Mullins, JI ;
Delwart, EL ;
CheingsongPopov, R ;
Kaleebu, P ;
Myers, G ;
Korber, BTM ;
Chiphangwi, J ;
Taha, T ;
Desormeaux, J ;
Eiumtrakul, S ;
Natpratan, C ;
Khamboonruang, C ;
Miotti, P ;
Halsey, NA ;
Vlahov, D ;
Nelson, KE ;
Phair, J ;
Cao, Y ;
Moore, JP ;
Ho, DD .
JOURNAL OF VIROLOGY, 1996, 70 (03) :1651-1667
[10]   HIV-1 INHIBITION BY A PEPTIDE [J].
JIANG, SB ;
LIN, K ;
STRICK, N ;
NEURATH, AR .
NATURE, 1993, 365 (6442) :113-113