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Potent HIV-1 Protease Inhibitors Containing Carboxylic and Boronic Acids: Effect on Enzyme Inhibition and Antiviral Activity and Protein-Ligand X-ray Structural Studies |
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| Authors: | Prof. Dr. Arun K. Ghosh Dr. Zilei Xia Dr. Satish Kovela William L. Robinson Megan E. Johnson Daniel W. Kneller Yuan-Fang Wang Dr. Manabu Aoki Yuki Takamatsu Prof. Dr. Irene T. Weber Dr. Hiroaki Mitsuya |
| Affiliation: | 1. Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, IN, 47907 USA;2. Departments of Biology and Chemistry, Molecular Basis of Disease, Georgia State University, Atlanta, GA, 30303 USA;3. Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892 USA Department of Refractory Viral Infections, National Center for Global Heath and Medicine Research Institute, Shinjuku, Tokyo, 162-8655 Japan;4. Department of Refractory Viral Infections, National Center for Global Heath and Medicine Research Institute, Shinjuku, Tokyo, 162-8655 Japan;5. Departments of Hematology and Infectious Diseases, Kumamoto University School of Medicine, Kumamoto, 860-8556 Japan Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, MD, 20892 USA Department of Refractory Viral Infections, National Center for Global Heath and Medicine Research Institute, Shinjuku, Tokyo, 162-8655 Japan |
| Abstract: | We report the synthesis and biological evaluation of phenylcarboxylic acid and phenylboronic acid containing HIV-1 protease inhibitors and their functional effect on enzyme inhibition and antiviral activity in MT-2 cell lines. Inhibitors bearing bis-THF ligand as P2 ligand and phenylcarboxylic acids and carboxamide as the P2′ ligands, showed very potent HIV-1 protease inhibitory activity. However, carboxylic acid containing inhibitors showed very poor antiviral activity relative to carboxamide-derived inhibitors which showed good antiviral IC50 value. Boronic acid derived inhibitor with bis-THF as the P2 ligand showed very potent enzyme inhibitory activity, but it showed lower antiviral activity than darunavir in the same assay. Boronic acid containing inhibitor with a P2-Crn-THF ligand also showed potent enzyme Ki but significantly decreased antiviral activity. We have evaluated antiviral activity against a panel of highly drug-resistant HIV-1 variants. One of the inhibitors maintained good antiviral activity against HIVDRVRP20 and HIVDRVRP30 viruses. We have determined high resolution X-ray structures of two synthetic inhibitors bound to HIV-1 protease and obtained molecular insight into the ligand-binding site interactions. |
| Keywords: | brain penetration drug resistance genetic barriers HIV-1 protease inhibitors structure-based design |