title: Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies.
abstract: Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.
authors: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors: Arun K
authors: AK
authors: Ghosh
authors: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors: Cuthbert D
authors: CD
authors: Martyr
authors: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors: Heather L
authors: HL
authors: Osswald
authors: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors: Venkat Reddy
authors: VR
authors: Sheri
authors: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors: Luke A
authors: LA
authors: Kassekert
authors: Department of Chemistry and Department of Medicinal Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors: Shujing
authors: S
authors: Chen
authors: Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
authors: Johnson
authors: J
authors: Agniswamy
authors: Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
authors: Yuan-Fang
authors: YF
authors: Wang
authors: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556, Japan.|Center for Clinical Sciences, National Center for Global Health and Medicine , Tokyo 162-8655, Japan.
authors: Hironori
authors: H
authors: Hayashi
authors: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556, Japan.|Department of Medical Technology, Kumamoto Health Science University , Kumamoto 861-5598, Japan.|Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Manabu
authors: M
authors: Aoki
authors: Department of Biology, Molecular Basis of Disease, Georgia State University , Atlanta, Georgia 30303, United States.
authors: Irene T
authors: IT
authors: Weber
authors: Departments of Infectious Diseases and Hematology, Kumamoto University Graduate School of Biomedical Sciences , Kumamoto 860-8556, Japan.|Center for Clinical Sciences, National Center for Global Health and Medicine , Tokyo 162-8655, Japan.|Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health , Bethesda, Maryland 20892, United States.
authors: Hiroaki
authors: H
authors: Mitsuya
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D024921:Drug Resistance, Multiple, Viral; D005663:Furans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D013237:Stereoisomerism
chemical_list: D005663:Furans; D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1