title: Design and optimization of aspartate N-acetyltransferase inhibitors for the potential treatment of Canavan disease.
abstract: Canavan disease is a fatal neurological disorder caused by defects in the metabolism of N-acetyl-l-aspartate (NAA). Recent work has shown that the devastating symptoms of this disorder are correlated with the elevated levels of NAA observed in these patients, caused as a consequence of the inability of mutated forms of aspartoacylase to adequately catalyze its breakdown. The membrane-associated enzyme responsible for the synthesis of NAA, aspartate N-acetyltransferase (ANAT), has recently been purified and examined (Wang et al., Prot Expr Purif. 2016;119:11). With the availability, for the first time, of a stable and soluble form of ANAT we can now report the identification of initial inhibitors against this biosynthetic enzyme, obtained from the screening of several focused compound libraries. Two core structures of these moderate binding compounds have subsequently been optimized, with the most potent inhibitors in these series possessing sub-micromolar inhibition constants (Kivalues) against ANAT. Slowing the production of NAA via the inhibition of ANAT will lower the elevated levels of this metabolite and can potentially serve as a treatment option to moderate the symptoms of Canavan disease.
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, United States.
authors.forename: Bharani
authors.initials: B
authors.lastname: Thangavelu
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, United States.
authors.forename: Vinay
authors.initials: V
authors.lastname: Mutthamsetty
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, United States.
authors.forename: Qinzhe
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, United States. Electronic address: ron.viola@utoledo.edu.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Viola
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017825:Canavan Disease / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000123:Acetyltransferases; C046791:aspartate N-acetyltransferase
keywords: Aspartate N-acetyltransferase; Canavan disease; Enzyme inhibitors; Fragment based drug discovery; Structure-activity relationships