title: Antivirals that target the amino-terminal domain of HIV type 1 glycoprotein 41.
abstract: Functional and structural studies were made to assess whether a class of antiviral agents targets the N-terminal domain of the glycoprotein 41,000 (gp41) of human immunodeficiency virus type 1 (HIV-1). Previous experiments have shown that the amino-terminal peptide (FP-I; 23 amino acids, residues 519-541) of HIV-1 gp41 is cytolytic to both human erythrocytes (non-CD4+ cells) and Hut-78 cells (CD4+ lymphocytes). Accordingly, FP-I-induced hemolysis may be used as a surrogate assay for evaluating the role of the N-terminal gp41 domain in HIV-cell interactions. Here, we studied the blocking of FP-I-induced lysis of erythrocytes by the following anti-HIV agents: (1) IgG [i.e., anti-(518-541) IgG] raised to an immunoconjugate of Arg-FP-I, (2) apolipoprotein A-1 (apo A-1) and a peptide based on apo A-1, (3) dextran sulfate, (4) gp41 peptide (residues 637-666), and (5) anionic human serum albumins. Dose-response curves indicated that their relative potency in inhibiting FP-I-induced hemolysis was approximately correlated with their previously reported anti-HIV activity. Electron spin resonance (ESR) studies showed that FP-I spin labeled at the N-terminal alanine binds to anti-(518-541) IgG, dextran sulfate, and anionic albumins. The high in vitro antiviral activity and low cytotoxicity of these agents suggest that blocking membrane-FP-I interactions offers a novel approach for AIDS therapy or prophylaxis.
authors.affiliation: Department of Pediatrics, Drew University-King Medical Center/UCLA 90059, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Gordon
authors.forename: A J
authors.initials: AJ
authors.lastname: Waring
authors.forename: C C
authors.initials: CC
authors.lastname: Curtain
authors.forename: A
authors.initials: A
authors.lastname: Kirkpatrick
authors.forename: C
authors.initials: C
authors.lastname: Leung
authors.forename: K
authors.initials: K
authors.lastname: Faull
authors.forename: P W
authors.initials: PW
authors.lastname: Mobley
mesh_terms: D000595:Amino Acid Sequence; D000914:Antibodies, Viral; D000998:Antiviral Agents / Q000494:pharmacology*; D016632:Apolipoprotein A-I / Q000494:pharmacology; D016264:Dextran Sulfate / Q000494:pharmacology; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006461:Hemolysis; D006801:Humans; D018796:Immunoconjugates; D007074:Immunoglobulin G / Q000494:pharmacology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D012709:Serum Albumin / Q000494:pharmacology; D013113:Spin Labels
chemical_list: D000914:Antibodies, Viral; D000998:Antiviral Agents; D016632:Apolipoprotein A-I; D015700:HIV Envelope Protein gp41; D018796:Immunoconjugates; D007074:Immunoglobulin G; D010446:Peptide Fragments; D012709:Serum Albumin; D013113:Spin Labels; C076451:HIV envelope protein gp41 (519-541); D016264:Dextran Sulfate