Novel β‐Glucocerebrosidase Activators That Bind to a New Pocket at a Dimer Interface and Induce Dimerization

• Published in: Angewandte Chemie International Edition Vol. 60; no. 10; pp. 5436 - 5442
• Main Authors: Benz, Joerg, Rufer, Arne C., Huber, Sylwia, Ehler, Andreas, Hug, Melanie, Topp, Andreas, Guba, Wolfgang, Hofmann, Eva Carolina, Jagasia, Ravi, Rodríguez Sarmiento, Rosa María
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.03.2021; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: activators; Cellular structure; Central nervous system; Chemistry; Chemistry, Multidisciplinary; Crystal structure; Data links; Dimerization; Dimers; Endoplasmic reticulum; Gaucher's disease; Glucosylceramidase; Molecular structure; Movement disorders; Neurodegenerative diseases; non inhibitory modulator binding site; Parkinson's disease; Physical Sciences; Pyrazine; Pyrazines; Science & Technology; structure elucidation; Substrates; Ultracentrifugation; β-glucocerebrosidase; beta-glucocerebrosidase; ENZYME; activators; GENE; PHARMACOLOGICAL CHAPERONES; non inhibitory modulator binding site; dimerization; structure elucidation; ALPHA-SYNUCLEIN; DISCOVERY; GAUCHER-DISEASE; PARKINSONS-DISEASE; β-glucocerebrosidase
• ISSN: 1433-7851; 1521-3773; 1521-3773
• DOI: 10.1002/anie.202013890

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. A first crystal structure for a novel GCase activator is obtained and a novel non‐inhibitory binding mode at a dimer interface, rationalizing the observed structure–activity relationship, is identified. Mechanistic insights and key information for future drug discovery efforts towards GCase activation are provided.