title: Current developments in the synthesis and biological activity of HIV-1 double-drug inhibitors.
abstract: A combination of different HIV inhibitors into a single molecular entity is a strategy that is growing in popularity in HIV-chemotherapy research. The high levels of resistance elicited by both nucleoside and non-nucleoside reverse transcriptase inhibitors has prompted the design of double-drugs combining these two entities with the aim of addressing the emergence of resistance. The strategy involves combining two different inhibitors into a single chemical entity via a linker, with the aim of improving the physicochemical characteristics of the individual compounds. Linkers may be sub-divided into cleavable and non-cleavable. While the former result in regeneration of the parent drugs of the double-drug once in the cell cytoplasm, the latter type is designed to allow the double-drug to target two active sites in a simultaneous or bifunctional fashion, which are located in close proximity. The linkers have been attached at the C-5', C-5 or N-3 positions of the nucleoside, and in some of the substrates synthesized, a synergistic anti-HIV activity has been observed. This review focuses on the design and synthesis of anti-HIV double-drugs reported to date.
authors.affiliation: Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
authors.forename: Clare I
authors.initials: CI
authors.lastname: Muhanji
authors.forename: Roger
authors.initials: R
authors.lastname: Hunter
mesh_terms: D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D019281:Dimerization; D004338:Drug Combinations; D015195:Drug Design; D004359:Drug Therapy, Combination; D005699:Galactosylceramides / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis; D015497:HIV-1 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000627:therapeutic use; D006801:Humans; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use
chemical_list: D044966:Anti-Retroviral Agents; D001596:Benzylamines; D000080027:Cyclams; D004338:Drug Combinations; D005699:Galactosylceramides; D023581:HIV Fusion Inhibitors; D017320:HIV Protease Inhibitors; D006571:Heterocyclic Compounds; D018894:Reverse Transcriptase Inhibitors; C088327:plerixafor