title: Optimisation of the degree of sulfation of a polymer based construct to block the entry of HIV-1 into cells.
abstract: Blocking the entry of HIV-1 into CD4+ cells is an important new therapeutic target for the development of novel vaginal microbicides. In this study, sulfated derivatives of the linear polysaccharide dextrin were synthesised whose percentage sulphation increased incrementally from 7.4 to 48.3%. Their anti-HIV-1 activity in C8166 cells was first seen when percentage sulfation reached 33.2%, but it was only seen in peripheral blood mononuclear cells when it reached 36.3%. It did not increase further when sulfation reached 40.2%. Primary viruses with a V3 loop charge of greater than +5 were blocked by 80 microg/ml of dextrin 2 sulfate but primary viruses with a V3 loop charge of less than +3 required 1,600 microg/ml to block viral entry effectively. Our results identify the relative contribution of the percentage sulfation of a polymer based construct for optimising its anti-HIV-1 activity whilst minimising its toxicity. A better understanding of these structure-function relationships will inform the design and development of novel vaginal microbicides to effectively block the sexual transmission of all primary viral isolates of HIV-1.
authors.affiliation: Faculty of Medicine, Department of Infectious Diseases, Imperial College London, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. s.shaunak@imperial.ac.uk
authors.forename: Sunil
authors.initials: S
authors.lastname: Shaunak
authors.forename: Mark
authors.initials: M
authors.lastname: Thornton
authors.forename: Ian
authors.initials: I
authors.lastname: Teo
authors.forename: Becky
authors.initials: B
authors.lastname: Chandler
authors.forename: Mick
authors.initials: M
authors.lastname: Jones
authors.forename: Sarah
authors.initials: S
authors.lastname: Steel
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002460:Cell Line; D003912:Dextrins / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011108:Polymers; D013329:Structure-Activity Relationship; D013431:Sulfates / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D019380:Anti-HIV Agents; D000925:Anticoagulants; D003912:Dextrins; D011108:Polymers; D013431:Sulfates