TY - JOUR
T1 - A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency
AU - Aoki, Manabu
AU - Hayashi, Hironori
AU - Rao, Kalapala Venkateswara
AU - Das, Debananda
AU - Higashi-Kuwata, Nobuyo
AU - Bulut, Haydar
AU - Aoki-Ogata, Hiromi
AU - Takamatsu, Yuki
AU - Yedidi, Ravikiran S.
AU - Davis, David A.
AU - Hattori, Shin Ichiro
AU - Nishida, Noriko
AU - Hasegawa, Kazuya
AU - Takamune, Nobutoki
AU - Nyalapatla, Prasanth R.
AU - Osswald, Heather L.
AU - Jono, Hirofumi
AU - Saito, Hideyuki
AU - Yarchoan, Robert
AU - Misumi, Shogo
AU - Ghosh, Arun K.
AU - Mitsuya, Hiroaki
N1 - Funding Information:
The present work was supported in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (HM and RY); a grant from the National Institutes of Health (GM53386; AKG); a grant for Development of Novel Drugs for Treating HIV-1 Infection and AIDS from Japan Agency for Medical Research and Development (HM); grants from Japan Society for the Promotion of Sciences; and a grant from National Center for Global Health and Medicine Research Institute. The authors also thank the synchrotron beam line staff at SPring-8 for their support in X-ray diffraction data collection and the support by the Platform Project for Supporting in Drug Discovery and Life Science Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http:// hpc.nih.gov).
Publisher Copyright:
© 2017, eLife Sciences Publications Ltd. All rights reserved.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.7554/ELIFE.28020
DO - 10.7554/ELIFE.28020
M3 - Article
AN - SCOPUS:85071396307
VL - 6
JO - eLife
JF - eLife
SN - 2050-084X
M1 - e28020
ER -
