title: The bicyclams, a new class of potent human immunodeficiency virus inhibitors, block viral entry after binding.
abstract: The bicyclams represent a new class of highly potent and selective HIV inhibitors. Time-of-addition experiments have previously shown that these compounds interfere with an early event in the viral replicative cycle. Additional experiments have now been carried out in order to investigate in more detail the mechanism of action of these promising compounds. As described in this paper, PCR experiments revealed that no viral DNA was formed following viral infection, thus confining the target(s) of action of the bicyclams to an early stage of HIV infection. An assay, using pseudotype virions containing the envelope of HIV-1 and the genome of a plaque-forming virus (Cocal Virus), pointed to viral entry as the main target of the bicyclams. HIV-1 strains resistant to two prototype bicyclams, JM2763 and SID791 (JM3100), were raised. Results obtained with SID791 with respect to syncytium formation induced by SID791-sensitive and -resistant HIV-1 strains and the cross-resistance observed for dextran sulfate, suggest inhibition of binding and/or fusion as a plausible target of SID791. Additional experiments enabled us to exclude SID791 and JM2763 as binding inhibitors and to conclude that bicyclams block the entry of cell-bound virus. Furthermore, a monoclonal antibody recognising the V3 loop of wild-type gp120 did not bind to this region in the two bicyclam-resistant strains. Our results point to gp120 as a possible target for the HIV-inhibitory effects of the bicyclams.
authors: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors: K
authors: K
authors: De Vreese
authors: D
authors: D
authors: Reymen
authors: P
authors: P
authors: Griffin
authors: A
authors: A
authors: Steinkasserer
authors: G
authors: G
authors: Werner
authors: G J
authors: GJ
authors: Bridger
authors: J
authors: J
authors: Esté
authors: W
authors: W
authors: James
authors: G W
authors: GW
authors: Henson
authors: J
authors: J
authors: Desmyter
authors: J
authors: J
authors: Anné
authors: I
authors: I
authors: De Clercq
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001569:Benzodiazepines / Q000494:pharmacology; D001596:Benzylamines; D000080027:Cyclams; D017931:DNA Primers; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D004352:Drug Resistance, Microbial; D015726:Giant Cells; D015483:HIV Antibodies / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000998:Antiviral Agents; D001596:Benzylamines; D000080027:Cyclams; D017931:DNA Primers; D004279:DNA, Viral; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D006571:Heterocyclic Compounds; D007093:Imidazoles; C097727:JM 2763; D010446:Peptide Fragments; C086147:R 86183; D001569:Benzodiazepines; C088327:plerixafor