In:
Angewandte Chemie, Wiley, Vol. 133, No. 10 ( 2021-03), p. 5496-5502
Abstract:
Genetic, preclinical and clinical data link Parkinson's disease and Gaucher's disease and provide a rational entry point to disease modification therapy via enhancement of β‐Glucocerebrosidase (GCase) activity. We discovered a new class of pyrrolo[2,3‐b]pyrazine activators effecting both Vmax and Km. They bind to human GCase and increase substrate metabolism in the lysosome in a cellular assay. We obtained the first crystal structure for an activator and identified a novel non‐inhibitory binding mode at the interface of a dimer, rationalizing the observed structure–activity relationship (SAR). The compound binds GCase inducing formation of a dimeric state at both endoplasmic reticulum (ER) and lysosomal pHs, as confirmed by analytical ultracentrifugation. Importantly, the pyrrolo[2,3‐b] pyrazines have central nervous system (CNS) drug‐like properties. Our findings are important for future drug discovery efforts in the field of GCase activation and provide a deeper mechanistic understanding of the requirements for enzymatic activation, pointing to the relevance of dimerization.
Type of Medium:
Online Resource
ISSN:
0044-8249
,
1521-3757
DOI:
10.1002/ange.v133.10
DOI:
10.1002/ange.202013890
Language:
English
Publisher:
Wiley
Publication Date:
2021
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