Identification of a selective inhibitor of murine intestinal alkaline phosphatase (ML260) by concurrent ultra-high throughput screening against human and mouse isozymes |
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| Institution: | 1. Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, United States;2. UCLA School of Medicine, Los Angeles, CA 90095, United States;3. Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;1. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC;2. Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC;4. Department of Medicine, Medical University of South Carolina, Charleston, SC;3. Department of Dermatology, Johannes Gutenberg University, Mainz, Germany;1. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi ‘Aldo Moro’ di Bari, Via Orabona 4, 70126 Bari, Italy;2. Università degli Studi di Firenze, Dipartimento di Chimica, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy;3. Università degli Studi di Firenze, Neurofarba Dept., Section of Pharmaceutical and Nutriceutical Sciences, Via U. Schiff 6, 50019 Sesto Fiorentino (Firenze), Italy;1. Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan;2. Department of Pharmaceutical Chemistry, University of Dhaka, Dhaka 1000, Bangladesh;3. Pharmacy Discipline, Life Science School, Khulna University, Khulna 9208, Bangladesh;1. Department of Chemistry & Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;2. Molecular Simulation Engineering (MOSE) Laboratory, DI3, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;1. Departamento de Investigación en Polímeros y Materiales (DIPM), Universidad de Sonora, Calle Rosales y Blvd. Luis Encinas s/n, Col. Centro, Hermosillo, Sonora 83000, Mexico;2. Departamento de Ciencias Químico-Biológicas, Universidad de Sonora, Calle Rosales y Blvd. Luis Encinas s/n, Col. Centro, Hermosillo, Sonora 83000, Mexico;3. Departamento de Física, Universidad de Sonora, Calle Rosales y Blvd. Luis Encinas s/n, Col. Centro, Hermosillo, Sonora 83000, Mexico;4. Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, México, D. F. 04510, Mexico;5. Laboratorio de Estructura Biomolecular, Centro de Investigación en Alimentación y Desarrollo (CIAD), A.C., Carretera a Ejido La Victoria Km 0.6, Hermosillo, Sonora 83304, Mexico |
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| Abstract: | Alkaline phosphatase (AP) isozymes are present in a wide range of species from bacteria to man and are capable of dephosphorylation and transphosphorylation of a wide spectrum of substrates in vitro. In humans, four AP isozymes have been identified—one tissue-nonspecific (TNAP) and three tissue-specific—named according to the tissue of their predominant expression: intestinal (IAP), placental (PLAP) and germ cell (GCAP) APs. Modulation of activity of the different AP isozymes may have therapeutic implications in distinct diseases and cellular processes. For instance, changes in the level of IAP activity can affect gut mucosa tolerance to microbial invasion due to the ability of IAP to detoxify bacterial endotoxins, alter the absorption of fatty acids and affect ectopurinergic regulation of duodenal bicarbonate secretion. To identify isozyme selective modulators of the human and mouse IAPs, we developed a series of murine duodenal IAP (Akp3-encoded dIAP isozyme), human IAP (hIAP), PLAP, and TNAP assays. High throughput screening and subsequent SAR efforts generated a potent inhibitor of dIAP, ML260, with specificity for the Akp3-, compared to the Akp5- and Akp6-encoded mouse isozymes. |
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| Keywords: | Alkaline phosphatase Inhibitors Enzymes Intestinal alkaline phosphatase Inflammatory bowel disease |
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