New perspectives for the chemotherapy and chemoprophylaxis of AIDS (acquired immune deficiency syndrome).
Various new classes of compounds have been recently identified as potent and selective inhibitors of acute HIV infection in vitro. As a rule, these compounds inhibit HIV replication at a concentration of 0.1-1 micrograms/ml, while not being toxic to the host cells at concentrations up to 500 micrograms/ml or higher. Some of the compounds even inhibit HIV replication at a concentration of a few nanograms per ml, thus achieving selectivity indexes up to 100,000, which makes them particularly promising drug candidates for the chemotherapy and -prophylaxis of HIV infections in vitro. These new candidate drugs for the treatment of AIDS fall into the following categories: (i) polyanions (polysulfates, polysulfonates, polycarboxylates and polyoxometalates), which interfere with virus attachment to the cell membrane; (ii) some plant lectins and modified (i.e. succinylated) albumins, which may directly interact with the fusion of the viral envelope with the cell membrane; (iii) bicyclam derivatives, which seem to be targeted at the uncoating (disassembly of the viral proteins from the viral RNA genome); and (iv) reverse transcriptase (RT) inhibitors which fall into two subcategories. The phosphonylmethoxyalkyl derivatives PMEA and FPMPA interact, as chain terminators, with the RT substrate binding site, as do azidothymidine (AZT) and the other dideoxynucleoside analogues. The TIBO derivatives and their congeners interact with a non-substrate binding site at the HIV-1 RT, and thus behave as allosteric inhibitors of the enzyme. The TIBO congeners have proved to be highly specific inhibitors of HIV-1 replication.
De Clercq
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Department of Human Biology, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000517:prevention & control; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006678:HIV / Q000187:drug effects*; D006801:Humans; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014760:Viral Fusion Proteins / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D014760:Viral Fusion Proteins