Novel concepts in the treatment of human immunodeficiency virus type 1 (HIV-1) infections by HIV-1-specific reverse transcriptase inhibitors.
Reverse transcriptase (RT) is an appropriate target for anti-HIV chemotherapy. In recent years several entirely new leads for the design of different structural classes of HIV-1-specific RT inhibitors were provided (also called non-nucleoside RT inhibitors or NNRTI). We performed profound studies on (i) the structure-antiviral activity relationship of TSAO (a prototype NNRTI compound), (ii) the biochemical and molecular mechanism of anti-viral action of TSAO and other NNRTI's, (iii) metabolism and antimetabolic effects of TSAO's in cell culture, and (iv) the pharmacokinetic properties of TSAO in mice. In addition, the molecular basis of resistance development of HIV-1 RT against other NNRTI's have also been profoundly studied. A mapping of the resistance mutations in the binding pocket of the RT and the sensitivity/resistance spectrum of the most important NNRTI's that are subject of clinical trials have been determined. Based on the information that became evident from these studies, a molecular model of interaction of the NNRTI inhibitor TSAO with the binding pocket in the HIV-1 reverse transcriptase has been proposed, and now provide the rational basis for the development of second generation TSAO molecules that may become suppressive to mutant HIV-1 strains. Also, resistance development could be markedly delayed, modulated, attenuated, or even fully suppressed by at least two different original approaches: (i) the knock-out drug concentration principle that exploits the limited capacity of mutant HIV-1 reverse transcriptases to respond to high NNRTI drug concentrations and (ii) the rational paired drug combination therapy that exploits the mutually exclusive sensitivity/resistance properties of NNRTI drugs against the different NNRTI-specific resistance mutations in the RT. Our findings have provided us with several powerful tools to have a more efficient chemotherapeutic impact on the HIV-1 infection and to better control the emergence of viral resistance.
Balzarini
J
J
Rega Instituut Katholieke Universiteit Leuven.
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D004351:Drug Resistance / Q000235:genetics; D015658:HIV Infections / Q000188:drug therapy*; D054303:HIV Reverse Transcriptase; D015497:HIV-1; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D017354:Point Mutation; D012194:RNA-Directed DNA Polymerase / Q000138:chemical synthesis; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D013936:Thymidine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D014529:Uridine / Q000031:analogs & derivatives
D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase; D013936:Thymidine; C075132:TSAO-T; D014529:Uridine