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Your search keyword '"Nobuyo Higashi-Kuwata"' showing total 2 results
Start Over Author "Nobuyo Higashi-Kuwata" Publisher elife sciences publications ltd
2 results on '"Nobuyo Higashi-Kuwata"'

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

Author

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

Subjects
drug-resistant HIV-1, protease inhibitor, CNS penetration, GRL-142, Medicine, Science, Biology (General), QH301-705.5
Abstract

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.

Published
2017
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2. A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency

Author

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

Subjects
Central Nervous System, 0301 basic medicine, CNS penetration, QH301-705.5, medicine.medical_treatment, Science, 030106 microbiology, Central nervous system, Human immunodeficiency virus (HIV), Microbial Sensitivity Tests, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Virus, protease inhibitor, Inhibitory Concentration 50, 03 medical and health sciences, HIV Protease, Drug Resistance, Viral, drug-resistant HIV-1, medicine, Animals, Humans, Potency, Biology (General), Cells, Cultured, Microbiology and Infectious Disease, Protease, General Immunology and Microbiology, Cell growth, GRL-142, General Neuroscience, HIV Protease Inhibitors, General Medicine, Virology, Rats, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, HIV-1, Medicine, Target protein, Intracellular, Research Article, Protein Binding
Abstract

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.

Published
2017

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