Targeting Conformational Flexibility of a Reactive Intermediate to Enhance Selectivity of a GABA Aminotransferase Inactivator.

ABSTRACT: Currently, mechanism-based inactivators (MBIs) are the only available therapeutic option to target γ-aminobutyric acid aminotransferase (GABA-AT). However, off-target activity against homologous enzymes is a well-recognized challenge for the clinical use of MBIs. For example, CPP-115, an MBI of GABA-AT that completed a Phase I clinical trial, also inactivates ornithine aminotransferase (OAT). Here, we present a comprehensive investigation of an OAT-specific inactivation mechanism for CPP-115 by integrating biochemical experiments, X-ray crystallography, and computational simulations. Unlike in GABA-AT, where CPP-115 forms a noncovalent tight-binding adduct only, a covalent adduct was additionally observed with human OAT (hOAT). Notably, the crystal structures of CPP-115-treated h

SUBMITTER: Kang KM 

PROVIDER: S-EPMC12927612 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature