Design and synthesis of trans-2-substituted-cyclopropane-1-carboxylic acids as the first non-natural small molecule inhibitors of O-acetylserine sulfhydrylase

Abstract

O-Acetylserine sulfhydrylase (isoform A, OASS-A) is a pyridoxal-5′-phosphate-dependent enzyme responsible for cysteine biosynthesis in many pathological microorganisms. It is proposed that inhibition of OASS-A could represent a novel strategy to overcome bacterial resistance to antibiotics. A class of 2-substituted-cyclopropane-1-carboxylic acids was synthesized, based on structural determinants grasped by analyzing a group of synthetic pentapeptides known to efficiently bind OASS-A from Haemophilus influenzae (HiOASS-A). The cyclopropane derivatives were submitted to a binding affinity assay with HiOASS-A and three of them, with Kdiss in the low micromolar range, showed higher affinity than the most active synthetic pentapeptide. Thus, in this communication we report the first example of potent non-natural small molecule inhibitors of HiOASS-A. In addition, a molecular modelling study suggested a possible inhibition mechanism, through which the new cyclopropane ligands block HiOASS-A. Noteworthily, the novel, small-sized, non-peptidic inhibitors retain the structural motifs of the bulky peptides, which are relevant for the enzyme inhibition.