Antiviral inhibition of the HIV-1 capsid protein

被引:189
作者
Tang, C
Loeliger, E
Kinde, I
Kyere, S
Mayo, K
Barklis, E
Sun, YN
Huang, MJ
Summers, MF
机构
[1] Univ Maryland, Howard Hughes Med Inst, Baltimore, MD 21250 USA
[2] Univ Maryland, Dept Chem & Biochem, Baltimore, MD 21250 USA
[3] Archill Pharmaceut, New Haven, CT 06511 USA
[4] Oregon Hlth Sci Univ, Vollum Inst, Portland, OR 97201 USA
[5] Oregon Hlth Sci Univ, Dept Microbiol, Portland, OR 97201 USA
关键词
HIV-1; antiviral inhibitors; capsid assembly; nuclear magnetic resonance;
D O I
10.1016/S0022-2836(03)00289-4
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
During the assembly stage of the human immunodeficiency virus (HIV) replication cycle, several thousand copies of the viral Gag polyprotein associate at the cell membrane and bud to form an immature, non-infectious virion. Gag is subsequently cleaved by the protease, which liberates the capsid proteins for assembly into the polyprotein shell of the central core particle (or capsid) of the mature virus. Viral infectivity is critically dependent on capsid formation and stability, making the capsid protein a potentially attractive antiviral target. We have identified compounds that bind to an apical site on the N-terminal domain of the HIV-1 capsid protein and inhibit capsid assembly in vitro. One compound, N-(3-chloro-4-methylphenyl)-NN'{2-[({5-[(dimethylamino)-methyl]-2-furyl}-methyl)-sulfanyl]ethyl}urea) (CAP-1), is well tolerated in cell cultures, enabling antiviral and mechanistic studies. CAP-1 inhibits HIV-1 infectivity in a dose-dependent manner, but does not interfere with viral entry, rev transcription, integration, proteolytic processing, or virus production, indicating a novel antiviral mechanism. Significantly, virus particles generated in the presence of CAP-1 exhibit heterogeneous sizes and abnormal core morphologies, consistent with inhibited CA-CA interactions during virus assembly and maturation. These findings lay the groundwork for the development of assembly inhibitors as a new class of therapeutic agents for the treatment of AIDS. (C) 2003 Elsevier Science Ltd. All rights reserved.
引用
收藏
页码:1013 / 1020
页数:8
相关论文
共 47 条
[1]   PRODUCTION OF ACQUIRED IMMUNODEFICIENCY SYNDROME-ASSOCIATED RETROVIRUS IN HUMAN AND NONHUMAN CELLS TRANSFECTED WITH AN INFECTIOUS MOLECULAR CLONE [J].
ADACHI, A ;
GENDELMAN, HE ;
KOENIG, S ;
FOLKS, T ;
WILLEY, R ;
RABSON, A ;
MARTIN, MA .
JOURNAL OF VIROLOGY, 1986, 59 (02) :284-291
[2]   Binding of small molecules to an adaptive protein-protein interface [J].
Arkin, MR ;
Randal, M ;
DeLano, WL ;
Hyde, J ;
Luong, TN ;
Oslob, JD ;
Raphael, DR ;
Taylor, L ;
Wang, J ;
McDowell, RS ;
Wells, JA ;
Braisted, AC .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (04) :1603-1608
[3]   HIV POPULATION-DYNAMICS IN-VIVO - IMPLICATIONS FOR GENETIC-VARIATION, PATHOGENESIS, AND THERAPY [J].
COFFIN, JM .
SCIENCE, 1995, 267 (5197) :483-489
[4]  
*DEL SCI, 2002, PYMOL MOL GRAPH SYST
[5]   Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids [J].
Deres, K ;
Schröder, CH ;
Paessens, A ;
Goldmann, S ;
Hacker, HJ ;
Weber, O ;
Krämer, T ;
Niewöhner, U ;
Pleiss, U ;
Stoltefuss, J ;
Graef, E ;
Koletzki, D ;
Masantschek, RNA ;
Reimann, A ;
Jaeger, R ;
Gross, R ;
Beckermann, B ;
Schlemmer, KH ;
Haebich, D ;
Rübsamen-Waigmann, H .
SCIENCE, 2003, 299 (5608) :893-896
[6]   FUNCTIONAL DOMAINS OF THE CAPSID PROTEIN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 [J].
DORFMAN, T ;
BUKOVSKY, A ;
OHAGEN, A ;
HOGLUND, S ;
GOTTLINGER, HG .
JOURNAL OF VIROLOGY, 1994, 68 (12) :8180-8187
[7]   ASSEMBLY OF RECOMBINANT HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 CAPSID PROTEIN INVITRO [J].
EHRLICH, LS ;
AGRESTA, BE ;
CARTER, CA .
JOURNAL OF VIROLOGY, 1992, 66 (08) :4874-4883
[8]   MULTIPLE EFFECTS OF MUTATIONS IN HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 INTEGRASE ON VIRAL REPLICATION [J].
ENGELMAN, A ;
ENGLUND, G ;
ORENSTEIN, JM ;
MARTIN, MA ;
CRAIGIE, R .
JOURNAL OF VIROLOGY, 1995, 69 (05) :2729-2736
[9]  
Ewing TJA, 1997, J COMPUT CHEM, V18, P1175, DOI 10.1002/(SICI)1096-987X(19970715)18:9<1175::AID-JCC6>3.0.CO
[10]  
2-O