A novel central nervous system-penetrating protease inhibitor overcomes human immunodeficiency virus 1 resistance with unprecedented aM to pM potency
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,
Hiroaki Mitsuya
Affiliations
Manabu Aoki
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States; Department of Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Rheumatology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Medical Technology, Kumamoto Health Science University, Kumamoto, Japan
Hironori Hayashi
National Center for Global Health and Medicine Research Institute, Tokyo, Japan
Kalapala Venkateswara Rao
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States; Department of Chemistry, Purdue University, West Lafayette, United States
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
Nobuyo Higashi-Kuwata
National Center for Global Health and Medicine Research Institute, Tokyo, Japan
Haydar Bulut
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
Hiromi Aoki-Ogata
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States; Department of Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Rheumatology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
Ravikiran S Yedidi
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
David A Davis
Retroviral Disease Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
Shin-ichiro Hattori
National Center for Global Health and Medicine Research Institute, Tokyo, Japan
Noriko Nishida
Bioanalysis Group, Drug Metabolism and Analysis Department, Nonclinical Research Center, Drug Development Service Segment, LSI Medience Corporation, Tokyo, Japan
Kazuya Hasegawa
Protein Crystal Analysis Division, Japan Synchrotron Radiation Research Institute, Hyogo, Japan
Nobutoki Takamune
Innovative Collaboration Organization, Kumamoto University, Kumamoto, Japan
Prasanth R Nyalapatla
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States; Department of Chemistry, Purdue University, West Lafayette, United States
Heather L Osswald
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States; Department of Chemistry, Purdue University, West Lafayette, United States
Hirofumi Jono
Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan
Hideyuki Saito
Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan
Robert Yarchoan
Retroviral Disease Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States
Shogo Misumi
Department of Environmental and Molecular Health Sciences, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
Arun K Ghosh
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, United States; Department of Chemistry, Purdue University, West Lafayette, United States
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, United States; Department of Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Rheumatology, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; Department of Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto, Japan; National Center for Global Health and Medicine Research Institute, Tokyo, Japan
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.
