دورية أكاديمية
Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration.
| العنوان: | Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration. |
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| المؤلفون: | Subramanian C; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Frank MW; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Sukhun R; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Henry CE; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Wade A; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Harden ME; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Rao S; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Tangallapally R; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Yun MK; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., White SW; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Lee RE; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.) richard.lee@stjude.org., Sinha U; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Rock CO; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.)., Jackowski S; Departments of Infectious Diseases (C.S., M.W.F., C.O.R., S.J.), Chemical Biology and Therapeutics (R.T., R.E.L.), Structural Biology (M.-K.Y., S.W.W.), and St. Jude Graduate School of Biomedical Sciences (S.W.W.), St. Jude Children's Research Hospital, Memphis, Tennessee; Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee (S.W.W., C.O.R.); and CoA Therapeutics, Inc., a BridgeBio Pharma, Inc. Company, Palo Alto, California (R.S., C.E.H., A.W., M.E.H., S.R., U.S.). |
| المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Jan 02; Vol. 388 (1), pp. 171-180. Date of Electronic Publication: 2024 Jan 02. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
| مواضيع طبية MeSH: | Pantothenate Kinase-Associated Neurodegeneration*/drug therapy , Pantothenate Kinase-Associated Neurodegeneration*/genetics, Mice ; Animals ; Rats ; Acetyl Coenzyme A/metabolism ; Acetyl Coenzyme A/therapeutic use ; Coenzyme A/metabolism ; Disease Models, Animal ; Phosphotransferases (Alcohol Group Acceptor)/genetics ; Brain/metabolism |
| مستخلص: | Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by a motor disorder with combinations of dystonia, parkinsonism, and spasticity, leading to premature death. PKAN is caused by mutations in the PANK2 gene that result in loss or reduction of PANK2 protein function. PANK2 is one of three kinases that initiate and regulate coenzyme A biosynthesis from vitamin B5, and the ability of BBP-671, an allosteric activator of pantothenate kinases, to enter the brain and elevate coenzyme A was investigated. The metabolic stability, protein binding, and membrane permeability of BBP-671 all suggest that it has the physical properties required to cross the blood-brain barrier. BBP-671 was detected in plasma, liver, cerebrospinal fluid, and brain following oral administration in rodents, demonstrating the ability of BBP-671 to penetrate the brain. The pharmacokinetic and pharmacodynamic properties of orally administered BBP-671 evaluated in cannulated rats showed that coenzyme A (CoA) concentrations were elevated in blood, liver, and brain. BBP-671 elevation of whole-blood acetyl-CoA served as a peripheral pharmacodynamic marker and provided a suitable method to assess target engagement. BBP-671 treatment elevated brain coenzyme A concentrations and improved movement and body weight in a PKAN mouse model. Thus, BBP-671 crosses the blood-brain barrier to correct the brain CoA deficiency in a PKAN mouse model, resulting in improved locomotion and survival and providing a preclinical foundation for the development of BBP-671 as a potential treatment of PKAN. SIGNIFICANCE STATEMENT: The blood-brain barrier represents a major hurdle for drugs targeting brain metabolism. This work describes the pharmacokinetic/pharmacodynamic properties of BBP-671, a pantothenate kinase activator. BBP-671 crosses the blood-brain barrier to correct the neuron-specific coenzyme A (CoA) deficiency and improve motor function in a mouse model of pantothenate kinase-associated neurodegeneration. The central role of CoA and acetyl-CoA in intermediary metabolism suggests that pantothenate kinase activators may be useful in modifying neurological metabolic disorders. (Copyright © 2023 by The Author(s).) |
| سلسلة جزيئية: | ClinicalTrials.gov NCT04836494 |
| المشرفين على المادة: | EC 2.7.1.33 (pantothenate kinase) 72-89-9 (Acetyl Coenzyme A) SAA04E81UX (Coenzyme A) EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)) |
| تواريخ الأحداث: | Date Created: 20231024 Date Completed: 20240104 Latest Revision: 20240313 |
| رمز التحديث: | 20240313 |
| DOI: | 10.1124/jpet.123.001919 |
| PMID: | 37875310 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1521-0103 |
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| DOI: | 10.1124/jpet.123.001919 |