A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency.
Manabu AokiHironori HayashiKalapala Venkateswara RaoDebananda DasNobuyo Higashi-KuwataHaydar BulutHiromi Aoki-OgataYuki TakamatsuRavikiran S YedidiDavid A DavisShin-Ichiro HattoriNoriko NishidaKazuya HasegawaNobutoki TakamunePrasanth R NyalapatlaHeather L OsswaldHirofumi JonoHideyuki SaitoRobert YarchoanShogo MisumiArun K GhoshHiroaki MitsuyaPublished in: eLife (2017)
Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced HIV-1 transmission at very high rates. However, certain individuals who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due to adverse effects and the emergence of drug-resistant HIV-1 variants. Here, we report GRL-142, a novel HIV-1 protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which has extremely potent activity against all HIV-1 strains examined with IC50 values of attomolar-to-picomolar concentrations, virtually no effects on cellular growth, extremely high genetic barrier against the emergence of drug-resistant variants, and favorable intracellular and central nervous system penetration. GRL-142 forms optimum polar, van der Waals, and halogen bond interactions with HIV-1 protease and strongly blocks protease dimerization, demonstrating that combined multiple optimizing elements significantly enhance molecular and atomic interactions with a target protein and generate unprecedentedly potent and practically favorable agents.
Keyphrases
- antiretroviral therapy
- hiv infected
- human immunodeficiency virus
- drug resistant
- hiv positive
- hiv aids
- hiv infected patients
- hepatitis c virus
- multidrug resistant
- hiv testing
- acinetobacter baumannii
- escherichia coli
- men who have sex with men
- gene expression
- copy number
- air pollution
- ionic liquid
- dna methylation
- protein protein
- combination therapy
- cystic fibrosis
- heavy metals