title: Anti-HIV-1 activity of combinations and covalent conjugates of negatively charged human serum albumins (NCAs) and AZT.
abstract: Negatively charged albumins (NCAs, with the prototypes Suc-HSA and Aco-HSA), modified proteins with a potent anti-HIV-1 activity in the nanomolar concentration range, were studied for several aspects of their antiviral mechanism. In addition we investigated the antiviral activity of combinations and covalent conjugates of these NCAs and the reverse transcriptase inhibitor AZT. Addition of NCAs to HIV-1-infected target cells in time-of-addition experiments could be delayed for 30 min after infection before significant loss of activity occurred. Syncytium formation of HIV-infected and uninfected T-cells was inhibited by the NCAs at concentrations of 1-4 microg/ml. The gp120-mediated virus/cell binding, however, was only inhibited by the NCAs at a 10-fold higher concentrations. The combined data are compatible with a preferential influence on virus/cell fusion. A subsynergistic activity against HIV-1 was observed with the non-covalent mixture of Aco-HSA and AZT. When AZT was covalently coupled to the NCAs, and added one hour after infection of the target cells, the anti-HIV-1 activity of NCA-AZTMP was diminished by only 2-6-fold, while this was diminished at least 120-fold for the NCAs. Furthermore the addition of NCA-AZTMP could be delayed up to at least 3 h after infection without loss of antiviral activity. It is concluded that AZT that was coupled to the NCAs significantly contributes to the overall antiviral activity of the conjugates leading to complementary effects. These results highlight the potential of using NCA-AZTMP as dual-targeting preparations against HIV-1 in which both the carrier and the coupled drug contribute to the therapeutic efficacy acting at a different level in the replication cycle.
authors.affiliation: Groningen Institute for Drug Studies, Section of Pharmacokinetics and Drug Delivery, University Centre for Pharmacy, The Netherlands.
authors.forename: M E
authors.initials: ME
authors.lastname: Kuipers
authors.forename: P J
authors.initials: PJ
authors.lastname: Swart
authors.forename: M
authors.initials: M
authors.lastname: Witvrouw
authors.forename: J A
authors.initials: JA
authors.lastname: Esté
authors.forename: D
authors.initials: D
authors.lastname: Reymen
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
mesh_terms: D000156:Aconitic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000925:Anticoagulants; D018929:Cell Culture Techniques; D054306:Dideoxynucleotides; D004338:Drug Combinations; D004355:Drug Stability; D004357:Drug Synergism; D015726:Giant Cells / Q000187:drug effects; D006801:Humans; D012709:Serum Albumin / Q000494:pharmacology*; D000075462:Serum Albumin, Human; D055672:Static Electricity; D013601:T-Lymphocytes / Q000187:drug effects; D013942:Thymine Nucleotides / Q000494:pharmacology*; D013997:Time Factors; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D000925:Anticoagulants; D054306:Dideoxynucleotides; D004338:Drug Combinations; D012709:Serum Albumin; D013942:Thymine Nucleotides; C108785:polyaconitylated human serum albumin; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine; D000156:Aconitic Acid; D000075462:Serum Albumin, Human