title: Synthesis, gp120 binding and anti-HIV activity of fatty acid esters of 1,1-linked disaccharides.
abstract: Inspired by the anti-human immunodeficiency virus (HIV) activity of analogues of β-galactosylceramide (GalCer), a set of mono- and di-saccharide fatty acid esters were designed as GalCer mimetics and their binding to the V3 loop peptide of HIV-1 and anti-HIV activity evaluated. 1,1-linked Gal-Man and Glu-Man disaccharides with an ester on the Man subunit bound the V3 loop peptide and inhibited HIV infectivity in single round infection assays with the TZM-bl cell line. IC(50)'s were in the 50 μM range with no toxicity to the cells at concentrations up to 200 μM. These compounds appear to inhibit virus entry at early steps in viral infection since they were inactive if added post viral entry. Although these compounds were found to bind to the V3 loop peptide of gp120, it is not clear that this interaction is responsible for their anti-HIV activity because the relative binding affinity of closely related analogues did not correlate with their antiviral behavior. The low cytotoxicity of these 1,1-linked disaccharide fatty acid esters, combined with the easy accessibility to structurally diverse analogues make these molecules attractive leads for new topical anti-viral agents.
authors.affiliation: Department of Chemistry, Hunter College, 695 Park Avenue, New York, NY 10021, USA.
authors.forename: Stewart
authors.initials: S
authors.lastname: Bachan
authors.forename: Jacques
authors.initials: J
authors.lastname: Fantini
authors.forename: Anjali
authors.initials: A
authors.lastname: Joshi
authors.forename: Himanshu
authors.initials: H
authors.lastname: Garg
authors.forename: David R
authors.initials: DR
authors.lastname: Mootoo
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D002460:Cell Line; D004187:Disaccharides / Q000138:chemical synthesis* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical; D004952:Esters / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006017:Glycolipids / Q000032:analysis; D006678:HIV / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D008823:Micelles; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects; D013329:Structure-Activity Relationship; D013499:Surface Properties
chemical_list: D000998:Antiviral Agents; D004187:Disaccharides; D004952:Esters; D005227:Fatty Acids; D005699:Galactosylceramides; D006017:Glycolipids; D015699:HIV Envelope Protein gp120; D008823:Micelles; D010455:Peptides; D019718:Receptors, CXCR4