Microbicides for multidrug-resistant and multitropic HIV-1.
The most common mode of acquiring HIV-1 is via sexual transmission across the genital mucosa. Topical microbicides are a promising prevention strategy for the protection against HIV infection and may ultimately have an impact on the global AIDS pandemic. The effectiveness of a microbicide to prevent HIV-1 transmission will depend on the evolutionary and genital transmission dynamics of the viral subtypes, and sexual behavioral characteristics. Contemporary antiretroviral therapy has led to virological failure as a result of HIV-1 reverse transcriptase gene mutations. The transmission of these multidrug-resistant HIV-1 variants, and the superinfection with the same or distinct HIV-1 subtypes and recombination is a formidable hindrance inherent to global microbicide development. Consequently, mechanism-based microbicides targeting both the cell-free and cell-associated HIV-1 variants and subtypes can be expected to have superior clinical efficacy and safety profiles compared with polymeric anionic microbicides. This review describes the discovery of potent anti-HIV-1 agents against multidrug-resistant and multitropic HIV-1 variants with implications for global microbicide development. Stampidine and thiourea non-nucleoside reverse transcriptase inhibitors (NNRTIs) have demonstrated highly potent activity against clinically relevant multidrug-resistant and recombinant HIV-1 isolates spanning different subtypes across several continents. Extensive preclinical studies have shown that stampidine and a candidate thiourea NNRTI (HI-443) have clinical potential as a safe combination microbicide to inhibit, prevent or treat mucosal HIV-1 infections.
D'Cruz
Osmond J
OJ
Paradigm Pharmaceuticals LLC, Drug Discovery Program, St Paul, MN 55113, USA. dcruz915@comcast.net
Uckun
Faith M
FM
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D054306:Dideoxynucleotides / Q000494:pharmacology / Q000627:therapeutic use; D024921:Drug Resistance, Multiple, Viral; D004359:Drug Therapy, Combination; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control / Q000635:transmission; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D018119:Stavudine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D013938:Thymidine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D054306:Dideoxynucleotides; C403248:HI 443; D011725:Pyridines; C472384:stampidine; D013938:Thymidine Monophosphate; D018119:Stavudine; D013890:Thiourea