A broad HIV-1 inhibitor blocks envelope glycoprotein transitions critical for entry

Nat Chem Biol. 2014 Oct;10(10):845-52. doi: 10.1038/nchembio.1623. Epub 2014 Aug 31.

Abstract

Binding to the primary receptor, CD4, triggers conformational changes in the metastable HIV-1 envelope glycoprotein (Env) trimer ((gp120-gp41)3) that are important for virus entry into host cells. These changes include an 'opening' of the trimer, creation of a binding site for the CCR5 co-receptor and formation and/or exposure of a gp41 coiled coil. Here we identify a new compound, 18A (1), that specifically inhibits the entry of a wide range of HIV-1 isolates. 18A does not interfere with CD4 or CCR5 binding, but it inhibits the CD4-induced disruption of quaternary structures at the trimer apex and the exposure of the gp41 HR1 coiled coil. Analysis of HIV-1 variants with increased or reduced sensitivity to 18A suggests that the inhibitor can distinguish distinct conformational states of gp120 in the unliganded Env trimer. The broad-range activity and observed hypersensitivity of resistant mutants to antibody neutralization support further investigation of 18A.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD4 Antigens / chemistry
  • CD4 Antigens / genetics
  • CD4 Antigens / metabolism
  • Cell Line, Transformed
  • Dose-Response Relationship, Drug
  • Gene Expression
  • HIV Envelope Protein gp120 / chemistry*
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp120 / metabolism
  • HIV Envelope Protein gp41 / chemistry*
  • HIV Envelope Protein gp41 / genetics
  • HIV Envelope Protein gp41 / metabolism
  • HIV Fusion Inhibitors / chemistry
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • HeLa Cells
  • Humans
  • Protein Binding
  • Protein Multimerization
  • Protein Structure, Quaternary / drug effects*
  • Receptors, CCR5 / chemistry
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / metabolism
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Semicarbazones / chemistry
  • Semicarbazones / pharmacology*
  • Thiadiazoles / chemistry
  • Thiadiazoles / pharmacology*
  • Viral Load / drug effects
  • Virus Internalization / drug effects*

Substances

  • 1-(2,1,3-benzothiadiazol-4-yl)-3-((E)-(4-hydroxyphenyl)methyleneamino)urea
  • CCR5 protein, human
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Receptors, CCR5
  • Recombinant Fusion Proteins
  • Semicarbazones
  • Thiadiazoles
  • gp120 protein, Human immunodeficiency virus 1
  • gp41 protein, Human immunodeficiency virus 1

Associated data

  • PubChem-Substance/196409802
  • PubChem-Substance/196409803
  • PubChem-Substance/196409804
  • PubChem-Substance/196409805
  • PubChem-Substance/196409806
  • PubChem-Substance/196409807
  • PubChem-Substance/196409808
  • PubChem-Substance/196409809
  • PubChem-Substance/196409810
  • PubChem-Substance/196409811
  • PubChem-Substance/196409812
  • PubChem-Substance/196409813
  • PubChem-Substance/196409814
  • PubChem-Substance/196409815
  • PubChem-Substance/196409816
  • PubChem-Substance/196409817
  • PubChem-Substance/196409818
  • PubChem-Substance/196409819
  • PubChem-Substance/196409820
  • PubChem-Substance/196409821
  • PubChem-Substance/196409822
  • PubChem-Substance/196409823
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  • PubChem-Substance/196409825
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  • PubChem-Substance/196409833
  • PubChem-Substance/196409834