Backbone modifications in peptidic inhibitors of flaviviral proteases |
| |
| Institution: | 1. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt;2. Department of Comparative Pathobiology, College of Veterinary Medicine, Purdue University, West Lafayette, IN, 47907, USA;3. Medicinal Chemistry, Institute of Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Im Neuenheimer Feld 364, 69120, Heidelberg, Germany;4. Center for Neuro-Medicine, Brain Science Institute, Korea Institute of Science and Technology (KIST), Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea;5. Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology (UST), Gajungro 217, Youseong-gu, Daejeon 305-350, Republic of Korea;6. Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Mutah University, Karak, 61710, Jordan;7. Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, 11566, Egypt;8. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, 32897, Egypt;9. Purdue Institute of Inflammation, Immunology, and Infectious Disease, West Lafayette, IN, 47907, USA;1. Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan;2. Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan;3. Department of Tropical Pediatrics, Faculty of Tropical Medicine, Mahidol University, 420/6 Ratchawithi Road, Ratchathewi, Bangkok 10400, Thailand;1. School of Pharmaceutical Sciences, and College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing 211816, PR China;2. Institute of Protein Research, Tongji University, Shanghai 200092, PR China;3. School of Life Sciences, Lanzhou University, Lanzhou 730000, PR China;4. Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, PR China;1. Sanford-Burnham-Prebys Medical Discovery Institute, Center for Neuroscience, Aging, and Stem Cell Research, La Jolla, CA 92037, United States;2. La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, United States;1. Wadsworth Center, New York State Department of Health, 120 New Scotland Ave, Albany, NY 12208, USA;2. National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD 20892, USA;3. Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA;4. Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, People''s Republic of China;5. Department of Biomedical Sciences, School of Public Health, University at Albany, PO Box 509, Empire State Plaza, Albany NY 12201, USA |
| |
| Abstract: | The NS2B-NS3 protease is a promising target for the development of drugs against dengue virus (DENV), West Nile virus (WNV) and related flaviviruses. We report the systematic variation of the peptide backbone of the two lead compounds Bz-Arg-Lys-d-Phg-NH2 and Bz-Arg-Lys-d-Phg(OBn)-NH2. While inhibitory activity against WNV protease was generally decreased, the inhibitory potency against DENV protease could be conserved and increased in several peptidomimetics, particularly in those containing a (NMe)arginine fragment or an N-terminal α-keto amide. Methylation at the α-position of the C-terminal phenylglycine led to a 6-fold higher potency against DENV protease. Peptidomimetics with modified backbone showed increased resistance against hydrolytic attack by trypsin and α-chymotrypsin. |
| |
| Keywords: | Dengue West Nile fever Flavivirus Protease inhibitor Peptidomimetics |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
