Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration.

Autor:	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.).
Jazyk:	angličtina
Zdroj:	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.
DOI:	10.1124/jpet.123.001919
Abstrakt:	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).)
Databáze:	MEDLINE
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