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Publication Abstract from PubMed

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.

Evaluation of a crystallographic surrogate for kallikrein 5 in the discovery of novel inhibitors for Netherton syndrome.,Thorpe JH, Edgar EV, Smith KJ, Lewell XQ, Rella M, White GV, Polyakova O, Nassau P, Walker AL, Holmes DS, Pearce AC, Wang Y, Liddle J, Hovnanian A Acta Crystallogr F Struct Biol Commun. 2019 May 1;75(Pt 5):385-391. doi:, 10.1107/S2053230X19003169. Epub 2019 Apr 26. PMID:31045568^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.