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

Angew Chem Int Ed Engl. 2021 Mar 1;60(10):5436-5442. doi: 10.1002/anie.202013890. Epub 2021 Jan 19.


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.

Keywords: activators; dimerization; non inhibitory modulator binding site; structure elucidation; β-glucocerebrosidase.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Enzyme Activators / chemistry
  • Enzyme Activators / metabolism*
  • Glucosylceramidase / chemistry
  • Glucosylceramidase / metabolism*
  • Humans
  • Kinetics
  • Molecular Structure
  • Protein Binding
  • Protein Multimerization / drug effects*
  • Pyrazines / chemistry
  • Pyrazines / metabolism*
  • Pyrroles / chemistry
  • Pyrroles / metabolism*
  • Structure-Activity Relationship


  • Enzyme Activators
  • Pyrazines
  • Pyrroles
  • Glucosylceramidase