Synthesis and structural insights into the binding mode of the albomycin δ1 core and its analogues in complex with their target aminoacyl-tRNA synthetase |
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| Institution: | 1. Medicinal Chemistry, Rega Institute for Medical Research, KU Leuven, Herestraat 49 Box 1041, B-3000 Leuven, Belgium;2. Biocrystallography, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Herestraat 49 Box 822, B-3000 Leuven, Belgium;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. Centro de Graduados e Investigación en Química, Tecnológico Nacional de México/IT de Tijuana, Tijuana, B.C., Mexico;2. Facultad de Ciencias Químicas e Ingeniería, Universidad Autónoma de Baja California Campus Tijuana, Tijuana, B.C., Mexico;3. Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán, Sin., Mexico;4. Cátedras Conacyt – Departamento de Investigación en Polímeros y Materiales, Universidad de Sonora, Hermosillo, Sonora, Mexico;5. Departamento de Ciencias Químico-Biológicas, Universidad de Sonora, Hermosillo, Sonora, Mexico;6. Environment and Health Research Unit, Autonomous University of Occident, Los Mochis, Sinaloa, Mexico;7. Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico;1. Department of Biochemistry, Faculty of Pharmacy, Egyptian Russian University, Badr 11829, Cairo, Egypt;2. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Cairo, Egypt;3. Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Helwan, Cairo, Egypt;4. Basic and Applied Sciences Institute, Egypt-Japan University of Science and Technology (E-JUST), New Borg El-Arab City, 21934 Alexandria, Egypt;5. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ain Shams University, Abbassia 11566, Cairo, Egypt;6. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Egypt;1. La Trobe Institute for Molecular Science, La Trobe University, Victoria 3086, Australia;2. School of Science, University of New South Wales, Canberra 2610, Australia;3. School of Chemistry, University of Wollongong, Wollongong, NSW 2522, Australia;4. Walter and Eliza Hall Institute, Parkville, Victoria 3052, Australia;5. Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia;1. Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, China;2. Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Department of Chemistry, Zhejiang Normal University, Jinhua 321004, China;1. Institute of New Drug Development, China Medical University, No. 91 Hsueh-Shih Rd., Taichung 40402, Taiwan;2. Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;3. School of Pharmacy, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;4. Master Program for Pharmaceutical Manufacture, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;5. Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, No. 91, Hsueh-Shih Rd., Taichung 40402, Taiwan;6. Department of Food Nutrition and Health Biotechnology, Asia University, Taichung 41354, Taiwan;7. Division of Metabolism, Department of Internal Medicine, China Medical University, Taichung 40402, Taiwan |
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| Abstract: | Despite of proven efficacy and well tolerability, albomycin is not used clinically due to scarcity of material. Several attempts have been made to increase the production of albomycin by chemical or biochemical methods. In the current study, we have synthesized the active moiety of albomycin δ1 and investigated its binding mode to its molecular target seryl-trna synthetase (SerRS). In addition, isoleucyl and aspartyl congeners were prepared to investigate whether the albomycin scaffold can be extrapolated to target other aminoacyl-tRNA synthetases (aaRSs) from both class I and class II aaRSs, respectively. The synthesized analogues were evaluated for their ability to inhibit the corresponding aaRSs by an in vitro aminoacylation experiment using purified enzymes. It was observed that the diastereomer having the 5′S, 6′R-configuration (nucleoside numbering) as observed in the crystal structure, exhibits excellent inhibitory activity in contrast to poor activity of its companion 5′R,6′S-diasteromer obtained as byproduct during synthesis. Moreover, the albomycin core scaffold seems well tolerated for class II aaRSs inhibition compared with class I aaRSs. To understand this bias, we studied X-ray crystal structures of SerRS in complex with the albomycin δ1 core structure 14a, and AspRS in complex with compound 16a. Structural analysis clearly showed that diastereomer selectivity is attributed to the steric restraints of the active site of SerRS and AspRS. |
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| Keywords: | Albomycin Albomycin analogues Aminoacyl-tRNA synthetase inhibitors Serine-tRNA synthetase X-ray crystallography Structural analysis Natural product synthesis |
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