4 years ago

A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency

Hiroaki Mitsuya, Kalapala Venkateswara Rao, Prasanth R Nyalapatla, David A Davis, Arun K Ghosh, Hideyuki Saito, Shogo Misumi, Noriko Nishida, Hiromi Aoki-Ogata, Debananda Das, Manabu Aoki, Yuki Takamatsu, Robert Yarchoan, Haydar Bulut, Nobuyo Higashi-Kuwata, Heather L Osswald, Shin-ichiro Hattori, Ravikiran S Yedidi, Kazuya Hasegawa, Nobutoki Takamune, Hironori Hayashi, Hirofumi Jono
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.

Publisher URL: https://elifesciences.org/articles/28020

DOI: 10.7554/eLife.28020

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