Development of bisubstrate analog inhibitors of aspartate N-acetyltransferase, a critical brain enzyme.
Chem Biol Drug Des
; 95(1): 48-57, 2020 01.
Article
en En
| MEDLINE
| ID: mdl-31260162
ABSTRACT
Canavan disease (CD) is a fatal leukodystrophy caused by mutations in the aspA gene coding for the enzyme aspartoacylase. Insufficient catalytic activity by this enzyme leads to the accumulation of its substrate, N-acetyl-l-aspartate (NAA), and diminished production of acetate in brain oligodendrocytes of patients with CD. There is growing evidence that this accumulation of NAA is the cause of many of the developmental defects observed in these patients. NAA is produced in the brain by a transacetylation reaction catalyzed by aspartate N-acetyltransferase (ANAT), and this membrane-associated enzyme has recently been purified as a soluble maltose binding protein fusion. Designing selective inhibitors against ANAT has the potential to slow the accumulation of NAA and moderate these developmental defects, and this is the goal of this project. Several bisubstrate analog inhibitors of ANAT have been synthesized that have achieved nanomolar level binding affinities against this enzyme. Truncated versions and fragments of these bisubstrate analog inhibitors have identified the essential structural elements needed for high binding affinity. More drug-like versions of these inhibitors can now be built, based on these essential core structures.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Acetiltransferasas
/
Ácido Aspártico
/
Enfermedad de Canavan
/
Inhibidores Enzimáticos
Límite:
Humans
Idioma:
En
Revista:
Chem Biol Drug Des
Asunto de la revista:
BIOQUIMICA
/
FARMACIA
/
FARMACOLOGIA
Año:
2020
Tipo del documento:
Article
País de afiliación:
Estados Unidos