Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome.
Acta Crystallogr F Struct Biol Commun
; 75(Pt 5): 385-391, 2019 May 01.
Article
en En
| MEDLINE
| ID: mdl-31045568
The inhibition of kallikrein 5 (KLK5) has been identified as a potential strategy for treatment of the genetic skin disorder Netherton syndrome, in which loss-of-function mutations in the SPINK5 gene lead to down-regulation of the endogenous inhibitor LEKTI-1 and profound skin-barrier defects with severe allergic manifestations. To aid in the development of a medicine for this target, an X-ray crystallographic system was developed to facilitate fragment-guided chemistry and knowledge-based drug-discovery approaches. Here, the development of a surrogate crystallographic system in place of KLK5, which proved to be challenging to crystallize, is described. The biochemical robustness of the crystallographic surrogate and the suitability of the system for the study of small nonpeptidic fragments and lead-like molecules are demonstrated.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores de Proteasas
/
Benzamidinas
/
Calicreínas
Idioma:
En
Revista:
Acta Crystallogr F Struct Biol Commun
Año:
2019
Tipo del documento:
Article
País de afiliación:
Reino Unido
Pais de publicación:
Estados Unidos