title: 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.
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.
authors.affiliation: Lindsley F. Kimball Research Institute, New York Blood Center, 310 E 67th St., New York, NY 10021, USA. sjiang@nybloodcenter.org
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Yuxian
authors.initials: Y
authors.lastname: He
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D015726:Giant Cells / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000096:biosynthesis*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D008958:Models, Molecular; D008970:Molecular Weight; D011487:Protein Conformation / Q000187:drug effects; D011758:Pyrroles / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000633:toxicity; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D011758:Pyrroles; D019718:Receptors, CXCR4; D011994:Recombinant Proteins