title: Membrane perturbing actions of HIV type 1 glycoprotein 41 domains are inhibited by helical C-peptides.
abstract: To study the membrane actions of various domains of HIV-1 glycoprotein 41,000 (gp41), synthetic peptides were prepared corresponding to the N-terminal fusion region (FP; gp41 residues 519-541), the nearby N-leucine zipper domain (N-peptides; DP-107; gp41 residues 560-597), the C-leucine zipper domain (C-peptides; DP-178; gp41 residues 645-680), and the viral envelope adjacent domain that partially overlaps DP-178 (Pre-TM; gp41 residues 671-690). With erythrocytes, FP, DP-107, and Pre-TM induced hemolysis and cell aggregation; the order for hemolytic activity was Pre-TM > FP > DP-107, but each was equally effective in aggregating cells at the highest peptide concentrations tested. DP-178 produced neither hemolysis nor aggregation, but efficiently reduced FP-, DP-107-, and Pre-TM-induced membrane actions. Fourier transform infrared spectroscopy indicated that the membrane perturbations of Pre-TM, as well as the ability of DP-178 to block membrane activities of other gp41 domains, are dependent on Pre-TM and DP-178 each maintaining helical conformations and tryptophans at residues 673, 677, and 679. These results suggest that the corresponding N-terminal fusion, N-leucine zipper, and viral membrane-adjacent regions of HIV-1 gp41 may similarly promote key membrane perturbations underlying the merging of the viral envelope with the cell surface. Further, the antiviral mechanism of exogenous DP-178 (clinically approved enfuvirtide) may be partially explained by its coordinate inhibition of the fusogenic actions of the FP, DP-107, and Pre-TM regions of gp41.
authors.affiliation: Chemistry Department, California State Polytechnic University, Pomona, CA 91768, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Mobley
authors.forename: Jay A
authors.initials: JA
authors.lastname: Barry
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Waring
authors.forename: Mark A
authors.initials: MA
authors.lastname: Sherman
authors.forename: Larry M
authors.initials: LM
authors.lastname: Gordon
mesh_terms: D002942:Circular Dichroism; D000077560:Enfuvirtide; D004903:Erythrocyte Aggregation / Q000502:physiology*; D004910:Erythrocyte Membrane / Q000821:virology; D015700:HIV Envelope Protein gp41 / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D015497:HIV-1 / Q000472:pathogenicity*; D006461:Hemolysis / Q000502:physiology; D006801:Humans; D016350:Leucine Zippers / Q000502:physiology*; D008561:Membrane Fusion / Q000502:physiology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D017550:Spectroscopy, Fourier Transform Infrared
chemical_list: D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide