A therapeutic approach to pantothenate kinase associated neurodegeneration

Lalit Kumar Sharma, Chitra Subramanian, Mi-Kyung Yun, Matthew W. Frank, Stephen W. White, Charles O. Rock, Richard E. Lee and Suzanne Jackowski ()
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Lalit Kumar Sharma: St. Jude Children’s Research Hospital
Chitra Subramanian: St. Jude Children’s Research Hospital
Mi-Kyung Yun: St. Jude Children’s Research Hospital
Matthew W. Frank: St. Jude Children’s Research Hospital
Stephen W. White: St. Jude Children’s Research Hospital
Charles O. Rock: St. Jude Children’s Research Hospital
Richard E. Lee: St. Jude Children’s Research Hospital
Suzanne Jackowski: St. Jude Children’s Research Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Pantothenate kinase (PANK) is a metabolic enzyme that regulates cellular coenzyme A (CoA) levels. There are three human PANK genes, and inactivating mutations in PANK2 lead to pantothenate kinase associated neurodegeneration (PKAN). Here we performed a library screen followed by chemical optimization to produce PZ-2891, an allosteric PANK activator that crosses the blood brain barrier. PZ-2891 occupies the pantothenate pocket and engages the dimer interface to form a PANK•ATP•Mg2+•PZ-2891 complex. The binding of PZ-2891 to one protomer locks the opposite protomer in a catalytically active conformation that is refractory to acetyl-CoA inhibition. Oral administration of PZ-2891 increases CoA levels in mouse liver and brain. A knockout mouse model of brain CoA deficiency exhibited weight loss, severe locomotor impairment and early death. Knockout mice on PZ-2891 therapy gain weight, and have improved locomotor activity and life span establishing pantazines as novel therapeutics for the treatment of PKAN.

Date: 2018
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DOI: 10.1038/s41467-018-06703-2

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