N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion

Antimicrob Agents Chemother. 2004 Nov;48(11):4349-59. doi: 10.1128/AAC.48.11.4349-4359.2004.

Abstract

A recently approved peptidic human immunodeficiency virus type 1 (HIV-1) fusion inhibitor, T-20 (Fuzeon; Trimeris Inc.), has shown significant promise in clinical application for treating HIV-1-infected individuals who have failed to respond to the currently available antiretroviral drugs. However, T-20 must be injected twice daily and is too expensive. Therefore, it is essential to develop orally available small molecule HIV-1 fusion inhibitors. By screening a chemical library consisting of "drug-like" compounds, we identified two N-substituted pyrroles, designated NB-2 and NB-64, that inhibited HIV-1 replication at a low micromolar range. The absence of the COOH group in NB-2 and NB-64 resulted in a loss of anti-HIV-1 activity, suggesting that this acid group plays an important role in mediating the antiviral activity. NB-2 and NB-64 inhibited HIV-1 fusion and entry by interfering with the gp41 six-helix bundle formation and disrupting the alpha-helical conformation. They blocked a d-peptide binding to the hydrophobic pocket on surface of the gp41 internal trimeric coiled-coil domain. Computer-aided molecular docking analysis has shown that they fit inside the hydrophobic pocket and that their COOH group interacts with a positively charged residue (K574) around the pocket to form a salt bridge. These results suggest that NB-2 and NB-64 may bind to the gp41 hydrophobic pocket through hydrophobic and ionic interactions and block the formation of the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. Therefore, NB-2 and NB-64 can be used as lead compounds toward designing and developing more potent small molecule HIV-1 fusion inhibitors targeting gp41.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • CD4 Antigens / metabolism
  • Cell Line
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Drug Evaluation, Preclinical
  • Enzyme-Linked Immunosorbent Assay
  • Giant Cells / drug effects
  • HIV Envelope Protein gp120 / biosynthesis
  • HIV Envelope Protein gp120 / genetics
  • HIV Envelope Protein gp41 / biosynthesis*
  • HIV Fusion Inhibitors / chemical synthesis*
  • HIV Fusion Inhibitors / pharmacology*
  • HIV Fusion Inhibitors / toxicity
  • HIV-1 / drug effects
  • HIV-1 / metabolism*
  • HIV-1 / pathogenicity
  • Humans
  • Models, Molecular
  • Molecular Weight
  • Protein Conformation / drug effects
  • Pyrroles / chemical synthesis*
  • Pyrroles / pharmacology*
  • Pyrroles / toxicity
  • Receptors, CXCR4 / immunology
  • Receptors, CXCR4 / metabolism
  • Recombinant Proteins / metabolism

Substances

  • CD4 Antigens
  • HIV Envelope Protein gp120
  • HIV Envelope Protein gp41
  • HIV Fusion Inhibitors
  • Pyrroles
  • Receptors, CXCR4
  • Recombinant Proteins