title: Targeting of antiviral drugs to T4-lymphocytes. Anti-HIV activity of neoglycoprotein-AZTMP conjugates in vitro.
abstract: The delivery of the anti-HIV agent 3'-azido-3'-deoxythymidine (AZT), in its 5'-monophosphate form, (in) to human T-lymphocyte MT-4 cells in vitro through covalent coupling to neoglycoproteins was investigated. In vivo application of this drug targeting concept may lead to increased efficacy and/or diminished side effects caused by AZT during the treatment of AIDS and ARC patients. The rationale for the design of the neoglycoprotein carriers is based on the existence of sugar recognizing lectins on T-lymphocytes. Using a phenyl-linkage between sugar and Human Serum Albumin (HSA), various mannose-, fucose-, galactose-and glucose-containing neoglycoproteins were synthesized. The intrinsic anti-HIV activity of these neoglycoproteins was tested in vitro in HIV-1 infected MT-4 cells. Only the derivative having 40 moles mannose per mole protein (Man40HSA) shows pronounced anti-HIV-1 activity itself. This effect may be caused by interference of the Man40HSA with the gp120-CD4 mediated virus/MT-4 cell interaction. After conjugation with AZTMP, the mannose- as well as the fucose- and galactose-containing conjugates exhibited a pronounced activity. Conjugates of glucose-HSA and HSA displayed much less activity in spite of the fact that drug loading was considerably higher, compared with the galactose, mannose and fucose derivatives. In the series of mannose-neoglycoproteins, the Man22HSA-AZTMP conjugate was shown to be more than 30 times as active against HIV-1 compared to HSA-AZTMP. Selectivity indices of Man7 and Man22HSA-AZTMP were exceeding the AZT and AZTMP indices, indicating that these conjugates possess a more selective action. Stability experiments indicate that the potent action of the galactose-, mannose- and fucose-HSA-AZTMP conjugates is not due to a complete extracellular hydrolysis of the covalent drug-protein bond. Since Man22HSA has no intrinsic activity in the concentration range used, the antiviral effect is unlikely to be explained by synergism of the neoglycoprotein by a component of the cell membrane and subsequent internalization and release of the drug from the conjugate may play a role.
authors.affiliation: Department of Pharmacology & Therapeutics, Groningen University, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Molema
authors.forename: R W
authors.initials: RW
authors.lastname: Jansen
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: E
authors.initials: E
authors.lastname: de Clercq
authors.forename: D K
authors.initials: DK
authors.lastname: Meijer
mesh_terms: D000998:Antiviral Agents / Q000008:administration & dosage*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects*; D054306:Dideoxynucleotides; D004337:Drug Carriers; D006023:Glycoproteins / Q000138:chemical synthesis; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D008239:Lysine; D012709:Serum Albumin; D013942:Thymine Nucleotides / Q000008:administration & dosage*; D015215:Zidovudine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D054306:Dideoxynucleotides; D004337:Drug Carriers; D006023:Glycoproteins; D012709:Serum Albumin; D013942:Thymine Nucleotides; C057287:3'-azido-3'-deoxythymidine 5'phosphate; D015215:Zidovudine; D008239:Lysine