Home LiteratureArticle Details
PMID: 15016894 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155.

Journal of virology ·Vol. 78 ·No. 7 ·2004-04-00 ·Pages 3742-52

Madani N, Perdigoto AL, Srinivasan K, Cox JM, Chruma JJ, LaLonde J, Head M, Smith AB, Sodroski JG

Abstract

BMS-806 and the related compound, #155, are novel inhibitors of human immunodeficiency virus type 1 (HIV-1) entry that bind the gp120 exterior envelope glycoprotein. BMS-806 and #155 block conformational changes in the HIV-1 envelope glycoproteins that are induced by binding to the host cell receptor, CD4. We tested a panel of HIV-1 envelope glycoprotein mutants and identified several that were resistant to the antiviral effects of BMS-806 and #155. In the CD4-bound conformation of gp120, the amino acid residues implicated in BMS-806 and #155 resistance line the "phenylalanine 43 cavity" and a water-filled channel that extends from this cavity to the inner domain. Structural considerations suggest a model in which BMS-806 and #155 bind gp120 prior to receptor binding and, upon CD4 binding, are accommodated in the Phe-43 cavity and adjacent channel. The integrity of the nearby V1/V2 variable loops and N-linked carbohydrates on the V1/V2 stem indirectly influences sensitivity to the drugs. A putative binding site for BMS-806 and #155 between the gp120 receptor-binding regions and the inner domain, which is thought to interact with the gp41 transmembrane envelope glycoprotein, helps to explain the mode of action of these drugs.

MeSH Terms
Amino Acid Substitution/genetics Animals Anti-HIV Agents/pharmacology Cell Line Dogs Drug Resistance, Viral/genetics HIV Envelope Protein gp120/chemistry,genetics,metabolism HIV-1/drug effects,physiology Humans Models, Molecular Phenylalanine/genetics,metabolism Piperazines/pharmacology Protein Structure, Tertiary
Chemicals
Anti-HIV Agents BMS-378806 HIV Envelope Protein gp120 Piperazines Phenylalanine
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Madani Navid
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute. Department of Pathology and Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115, USA.
Perdigoto Ana Luisa
Srinivasan Kumar
Cox Jason M
Chruma Jason J
LaLonde Judith
Head Martha
Smith Amos B
Sodroski Joseph G
References (50)
50 references, click to expand
  1. Resistance to neutralization by broadly reactive antibodies to the human immunodeficiency virus type 1 gp120 glycoprotein conferred by a gp41 amino acid change.
    J Virol. 1994 Feb;68(2):674-80 PMID: 7507184
  2. Probing the structure of the human immunodeficiency virus surface glycoprotein gp120 with a panel of monoclonal antibodies.
    J Virol. 1994 Jan;68(1):469-84 PMID: 7504741
  3. Human immunodeficiency virus type 1 neutralization is determined by epitope exposure on the gp120 oligomer.
    J Exp Med. 1995 Jul 1;182(1):185-96 PMID: 7540648
  4. Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor binding.
    J Virol. 1995 Sep;69(9):5723-33 PMID: 7543586
  5. Human monoclonal antibody 2G12 defines a distinctive neutralization epitope on the gp120 glycoprotein of human immunodeficiency virus type 1.
    J Virol. 1996 Feb;70(2):1100-8 PMID: 8551569
  6. Antibody cross-competition analysis of the human immunodeficiency virus type 1 gp120 exterior envelope glycoprotein.
    J Virol. 1996 Mar;70(3):1863-72 PMID: 8627711
  7. HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor.
    Science. 1996 May 10;272(5263):872-7 PMID: 8629022
  8. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5.
    Nature. 1996 Jun 20;381(6584):667-73 PMID: 8649512
  9. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates.
    Cell. 1996 Jun 28;85(7):1135-48 PMID: 8674119
  10. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5.
    Nature. 1996 Nov 14;384(6605):179-83 PMID: 8906795
  11. CD4-dependent, antibody-sensitive interactions between HIV-1 and its co-receptor CCR-5.
    Nature. 1996 Nov 14;384(6605):184-7 PMID: 8906796
  12. Core structure of gp41 from the HIV envelope glycoprotein.
    Cell. 1997 Apr 18;89(2):263-73 PMID: 9108481
  13. Atomic structure of the ectodomain from HIV-1 gp41.
    Nature. 1997 May 22;387(6631):426-30 PMID: 9163431
  14. QXP: powerful, rapid computer algorithms for structure-based drug design.
    J Comput Aided Mol Des. 1997 Jul;11(4):333-44 PMID: 9334900
  15. Atomic structure of a thermostable subdomain of HIV-1 gp41.
    Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12303-8 PMID: 9356444
  16. Replication and neutralization of human immunodeficiency virus type 1 lacking the V1 and V2 variable loops of the gp120 envelope glycoprotein.
    J Virol. 1997 Dec;71(12):9808-12 PMID: 9371651
  17. The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.
    Science. 1998 Jun 19;280(5371):1884-8 PMID: 9632381
  18. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.
    Nature. 1998 Jun 18;393(6686):648-59 PMID: 9641677
  19. The antigenic structure of the HIV gp120 envelope glycoprotein.
    Nature. 1998 Jun 18;393(6686):705-11 PMID: 9641684
  20. Enhanced expression, native purification, and characterization of CCR5, a principal HIV-1 coreceptor.
    J Biol Chem. 1999 Oct 1;274(40):28745-50 PMID: 10497246
  21. Capture of an early fusion-active conformation of HIV-1 gp41.
    Nat Struct Biol. 1998 Apr;5(4):276-9 PMID: 9546217
  22. Energetics of the HIV gp120-CD4 binding reaction.
    Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9026-31 PMID: 10922058
  23. Structures of HIV-1 gp120 envelope glycoproteins from laboratory-adapted and primary isolates.
    Structure. 2000 Dec 15;8(12):1329-39 PMID: 11188697
  24. Loss of a single N-linked glycan allows CD4-independent human immunodeficiency virus type 1 infection by altering the position of the gp120 V1/V2 variable loops.
    J Virol. 2001 Apr;75(7):3435-43 PMID: 11238869
  25. Envelope glycoprotein determinants of neutralization resistance in a simian-human immunodeficiency virus (SHIV-HXBc2P 3.2) derived by passage in monkeys.
    J Virol. 2001 May;75(9):4208-18 PMID: 11287570
  26. Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoprotein.
    J Virol. 2002 Oct;76(19):9888-99 PMID: 12208966
  27. Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites.
    J Virol. 2003 Feb;77(3):1666-71 PMID: 12525600
  28. The prefusogenic intermediate of HIV-1 gp41 contains exposed C-peptide regions.
    J Biol Chem. 2003 Feb 28;278(9):7573-9 PMID: 12486032
  29. Biochemical and genetic characterizations of a novel human immunodeficiency virus type 1 inhibitor that blocks gp120-CD4 interactions.
    J Virol. 2003 Oct;77(19):10528-36 PMID: 12970437
  30. A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding.
    Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):11013-8 PMID: 12930892
  31. Discovery of 4-benzoyl-1-[(4-methoxy-1H- pyrrolo[2,3-b]pyridin-3-yl)oxoacetyl]-2- (R)-methylpiperazine (BMS-378806): a novel HIV-1 attachment inhibitor that interferes with CD4-gp120 interactions.
    J Med Chem. 2003 Sep 25;46(20):4236-9 PMID: 13678401
  32. Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins.
    Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5036-41 PMID: 15051887
  33. Characterization of the reverse transcriptase from a new retrovirus (HTLV) produced by a human cutaneous T-cell lymphoma cell line.
    Virology. 1981 Jul 15;112(1):355-60 PMID: 6166122
  34. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS).
    Science. 1983 May 20;220(4599):868-71 PMID: 6189183
  35. Frequent detection and isolation of cytopathic retroviruses (HTLV-III) from patients with AIDS and at risk for AIDS.
    Science. 1984 May 4;224(4648):500-3 PMID: 6200936
  36. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus.
    Nature. 1984 Dec 20-1985 Jan 2;312(5996):763-7 PMID: 6096719
  37. T-lymphocyte T4 molecule behaves as the receptor for human retrovirus LAV.
    Nature. 1984 Dec 20-1985 Jan 2;312(5996):767-8 PMID: 6083454
  38. Identification and characterization of conserved and variable regions in the envelope gene of HTLV-III/LAV, the retrovirus of AIDS.
    Cell. 1986 Jun 6;45(5):637-48 PMID: 2423250
  39. Computer-assisted analysis of envelope protein sequences of seven human immunodeficiency virus isolates: prediction of antigenic epitopes in conserved and variable regions.
    J Virol. 1987 Feb;61(2):570-8 PMID: 2433466
  40. Rapid and efficient site-specific mutagenesis without phenotypic selection.
    Methods Enzymol. 1987;154:367-82 PMID: 3323813
  41. Generation of a neutralization-resistant variant of HIV-1 is due to selection for a point mutation in the envelope gene.
    Cell. 1988 Jul 1;54(1):57-63 PMID: 2838179
  42. Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells.
    J Biol Chem. 1990 Jun 25;265(18):10373-82 PMID: 2355006
  43. Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding.
    J Virol. 1990 Dec;64(12):5701-7 PMID: 2243375
  44. Effects of changes in gp120-CD4 binding affinity on human immunodeficiency virus type 1 envelope glycoprotein function and soluble CD4 sensitivity.
    J Virol. 1991 Sep;65(9):5007-12 PMID: 1870209
  45. Characterization of a discontinuous human immunodeficiency virus type 1 gp120 epitope recognized by a broadly reactive neutralizing human monoclonal antibody.
    J Virol. 1991 Nov;65(11):6188-93 PMID: 1717717
  46. Discontinuous, conserved neutralization epitopes overlapping the CD4-binding region of human immunodeficiency virus type 1 gp120 envelope glycoprotein.
    J Virol. 1992 Sep;66(9):5635-41 PMID: 1380099
  47. Effects of amino acid changes in the extracellular domain of the human immunodeficiency virus type 1 gp41 envelope glycoprotein.
    J Virol. 1993 May;67(5):2747-55 PMID: 8474172
  48. Characterization of conserved human immunodeficiency virus type 1 gp120 neutralization epitopes exposed upon gp120-CD4 binding.
    J Virol. 1993 Jul;67(7):3978-88 PMID: 7685405
  49. Functional and immunologic characterization of human immunodeficiency virus type 1 envelope glycoproteins containing deletions of the major variable regions.
    J Virol. 1993 Aug;67(8):4557-65 PMID: 8331723
  50. Changes in the cytopathic effects of human immunodeficiency virus type 1 associated with a single amino acid alteration in the ectodomain of the gp41 transmembrane glycoprotein.
    J Virol. 1994 Jul;68(7):4662-8 PMID: 8207841
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
DOI
10.1128/jvi.78.7.3742-3752.2004
Published
2004-04-00
Pages
3742-52
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC371073
Subset
IM
Grants
NIAID NIH HHS · R37 AI024755 · United States
NINDS NIH HHS · F32 NS43260 M · United States
NINDS NIH HHS · F32 NS043260 · United States
NIAID NIH HHS · AI39420 · United States
NIAID NIH HHS · R01 AI039420 · United States
NIGMS NIH HHS · P01 GM056550 · United States
NIGMS NIH HHS · P01-GM56550 · United States
NIAID NIH HHS · AI24755 · United States
External Links
PubMed source DOI: 10.1128/jvi.78.7.3742-3752.2004 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2