Exploration of the P3 region of PEXEL peptidomimetics leads to a potent inhibitor of the Plasmodium protease,plasmepsin V |
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| Affiliation: | 1. Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Ji’nan, Shandong 250012, China;2. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China;3. Institute of Criminal Science and Technology, Ji’nan Public Security Bureau, Ji’nan 250100, China;4. School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, China;1. Department of Chemistry, Hunter College, City University of New York, 695 Park Avenue, NY 10065, USA;2. Ph.D. Program in Chemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA;3. Ph.D. Program in Biochemistry, CUNY Graduate Center, 365 5th Avenue, New York, NY 10016, USA;4. Department of Chemistry, Lehman College, The City University of New York, Bronx, NY 10468, USA;5. Department of Natural Sciences, LaGuardia Community College, City University of New York, New York, NY 11101, USA;6. Department of Radiology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA;1. Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic;2. Department of Physical Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 812 37 Bratislava, Slovak Republic;3. Department of Organic Chemistry, Faculty of Science, Pavol Jozef Šafárik University, Moyzesova 11, 041 01 Košice, Slovak Republic;4. Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, 833 91 Bratislava, Slovak Republic;5. Institute of Experimental Endocrinology, Slovak Academy of Sciences, Vlárska 3, 833 06 Bratislava, Slovak Republic;1. State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Donghua University, Shanghai 201620, PR China;2. Department of Pharmaceutical Science and Technology, College of Chemistry and Biology, Donghua University, 2999 North Renmin Road, Shanghai 201620, PR China;3. Ningbo Dongmi Pharmaceutical Co., Ltd, Ningbo 315899, Zhejiang, PR China;4. Shanghai Xianhui Pharmaceutical Co., Ltd, Shanghai 200433, PR China |
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| Abstract: | The use of arginine isosteres is a known strategy to overcome poor membrane permeability commonly associated with peptides or peptidomimetics that possess this highly polar amino acid. Here, we apply this strategy to peptidomimetics that are potent inhibitors of the malarial protease, plasmepsin V, with the aim of enhancing their activity against Plasmodium parasites, and exploring the structure–activity relationship of the P3 arginine within the S3 pocket of plasmepsin V. Of the arginine isosteres trialled in the P3 position, we discovered that canavanine was the ideal and that this peptidomimetic potently inhibits plasmepsin V, efficiently blocks protein export and inhibits parasite growth. Structure studies of the peptidomimetics bound to plasmepsin V provided insight into the structural basis for the enzyme activity observed in vitro and provides further evidence why plasmepsin V is highly sensitive to substrate modification. |
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| Keywords: | Plasmepsin V Peptidomimetics Arginine isosteres Malaria PEXEL |
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