Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance

We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us...

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Published inChemical communications (Cambridge, England) Vol. 58; no. 84; pp. 11762 - 11782
Main Authors Ghosh, Arun K, Weber, Irene T, Mitsuya, Hiroaki
Format Journal Article
LanguageEnglish
Published England Royal Society of Chemistry 20.10.2022
Royal Society of Chemistry (RSC)
Subjects
Chemical bonds
Crystallography, X-Ray
Darunavir - chemistry
Darunavir - pharmacology
Drug Design
Drug Resistance
Drug Resistance, Viral
Ether - pharmacology
Ethers
Heterocyclic compounds
HIV Protease - chemistry
HIV Protease - pharmacology
HIV Protease Inhibitors - pharmacology
HIV-1
Hydrogen bonding
Peptides - pharmacology
Protease
Protease inhibitors
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Summary:We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us to create a variety of inhibitors incorporating fused ring polycyclic ethers and aromatic heterocycles to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease as well as van der Waals interactions with residues in the S2 and S2′ subsites. We have also incorporated specific functionalities to enhance van der Waals interactions in the S1 and S1′ subsites. The combined effects of these structural templates are critical to the inhibitors' exceptional potency and drug-like properties. We highlight here our molecular design strategies to promote backbone hydrogen bonding interactions to combat drug-resistance and specific design of polycyclic ether templates to mimic peptide-like bonds in the HIV-1 protease active site. Our medicinal chemistry and drug development efforts led to the development of new generation inhibitors significantly improved over darunavir and displaying unprecedented antiviral activity against multidrug-resistant HIV-1 variants. We describe design and syntheses of a new generation of exceptionally highly potent non-peptidic HIV-1 protease inhibitors.
Bibliography:Arun K. Ghosh received his BS and MS in Chemistry from the University of Calcutta and Indian Institute of Technology, Kanpur respectively. He obtained his PhD in 1985 at the University of Pittsburgh. He pursued postdoctoral research with Professor E. J. Corey at Harvard University (1985-1988). He was a research fellow at Merck Research Laboratories prior to joining the University of Illinois-Chicago as an assistant Professor in 1994. In 2005, he moved to Purdue University where he is currently the Ian P. Rothwell Distinguished Professor in Chemistry and Medicinal Chemistry. His research interests are in the areas of organic, bioorganic, drug-design, and medicinal chemistry.
Hiroaki Mitsuya received his MD and PhD from National Kumamoto University School of Medicine (Japan). Following training in oncology/hematology/immunology, he joined National Cancer Institute in Bethesda (USA) in 1982, where he has been Principal Investigator & Chief of Experimental Retrovirology Section since 1991 to present. He also served as Professor of Medicine and Chairman of Departments of Hematology/Rheumatology/Infectious Diseases at Kumamoto University from 1997 to 2016. He now serves as Director, National Center for Global Health & Medicine, Tokyo. His current research focuses on antiviral research for development of therapeutics for HIV/AIDS, hepatitis B, and SARS-CoV-2.
Irene T. Weber received her BS and MS from Cambridge University, England, and obtained her PhD in 1978 from Oxford University, England. She pursued postdoctoral research with Professor Thomas Steitz at Yale University. She was Professor of Microbiology and Immunology at Thomas Jefferson University in Philadelphia from 1991. She moved to Georgia State University, Atlanta, in 2001 where she is a Regents' Professor of Biology and Chemistry and Georgia Cancer Coalition Distinguished Cancer Scientist. Her research focuses on the structure and activity of enzymes.
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USDOE
ISSN:1359-7345
1364-548X
1364-548X
DOI:10.1039/d2cc04541a