Mass spectrometry-guided discovery of novel GCPII inhibitor scaffolds.

ABSTRACT:

Introduction

There is an unmet need for therapeutics with a novel mechanism to address Q9 symptoms associated with conditions where aberrant glutamatergic neurotransmission is presumed pathogenic. One enzyme of potential relevance is glutamate carboxypeptidase II (GCPII), a brain metallopeptidase with significantly upregulated activity in nervous tissues following neurodegeneration or injury. Current inhibitors are too polar and charged leading to minimal brain penetration necessitating high systemic doses or direct brain injection. Our efforts are focused on identifying new inhibitor scaffolds with favorable brain penetration.

Methods

Herein, we used a newly developed dual-stream liquid chromatography mass spectrometry (LC/MS/MS) substrate cleavage assay to screen two small

SUBMITTER: Wiseman R 

PROVIDER: S-EPMC12568586 | biostudies-literature | 2025

REPOSITORIES: biostudies-literature