title: Peptide and non-peptide HIV fusion inhibitors.
abstract: Fusion of the HIV envelope with the target cell membrane is a critical step of HIV entry into the target cell. The HIV envelope glycoprotein gp41 plays an important role in the fusion of viral and target cell membranes and serves as an attractive target for development of HIV fusion inhibitors. The extracellular domain of gp41 contains three important functional regions, i.e. fusion peptide (FP), N- and C-terminal heptad repeats (NHR and CHR, respectively). The FP region is composed of hydrophobic, glycine-rich residues that are essential for the initial penetration of the target cell membrane. NHR and CHR regions consist of hydrophobic residues, which have the tendency to form alpha-helical coiled coils. During the process of fusion of HIV or HIV-infected cells with uninfected cells, FP inserts into the target cell membrane and subsequently the NHR and CHR regions change conformations and associate with each other to form a fusion-active gp41 core. Peptides derived from NHR and CHR regions, designated N- and C-peptides, respectively, have potent inhibitory activity against HIV fusion by binding to the CHR and NHR regions, respectively, to prevent the formation of the fusion-active gp41 core. C-peptide may also bind to FP, thereby blocking its insertion into the target cell membrane. One of the C-peptides, T-20, which is in the phase III clinical trials, has potent in vivo activity against HIV infection and is expected to become the first peptide HIV fusion inhibitory drug in the near future. However, this peptide HIV fusion inhibitor lacks oral availability and is sensitive to the proteolytic digestion. Therefore, it is essential to develop small molecular non-peptide HIV fusion inhibitors having a mechanism of action similar to the C-peptides. One of the approaches in identifying the inhibitors is to use an immunological assay to screen chemical libraries for the compounds that potentially block the interaction between the NHR and CHR regions to form a fusion-active gp41 core. In combination with computer-aided molecular docking techniques, the first active non-peptide HIV fusion inhibitor targeting gp41, ADS-J1, was identified. Other potential candidates of non-peptide HIV fusion inhibitors have also been identified using different approaches. It is expected that both peptide and non-peptide HIV fusion inhibitors will be developed as new classes of anti-HIV drugs, which will be used alone or in combination with HIV reverse transcriptase and protease inhibitors, for the treatment of HIV infection and AIDS.
authors.affiliation: Lindsley F. Kimball Research Institute, the New York Blood Center, 310 East 67th Street, New York, NY 10021, USA. shibo_jiang@nybc.org
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Asim K
authors.initials: AK
authors.lastname: Debnath
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D002986:Clinical Trials as Topic; D017076:Computer-Aided Design; D015195:Drug Design; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009282:Naphthalenesulfonates / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014227:Triazines / Q000737:chemistry / Q000494:pharmacology; D014760:Viral Fusion Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; C098314:HIV envelope glycoprotein gp41 (593-603); D009282:Naphthalenesulfonates; D010446:Peptide Fragments; D014227:Triazines; D014760:Viral Fusion Proteins; C407145:ADS J1