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 were 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, showed higher affinity than the most active synthetic pentapeptide. Thus, in this communication we report the first example of potent 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. Noteworthy, the novel, small-sized, non-peptidic inhibitors retain the structural motifs of the bulky peptides, which are relevant for the enzyme inhibition.

Design and synthesis of trans-2-substituted-cyclopropane-1-carboxylic acids as the first non-natural small molecule inhibitors of O-acetylserine sulfhydrylase / Amori, Laura; S., Katkevica; Bruno, Agostino; Campanini, Barbara; Felici, Paolo; Mozzarelli, Andrea; Costantino, Gabriele. - In: MEDCHEMCOMM. - ISSN 2040-2503. - 3:(2012), pp. 1111-1116. [10.1039/c2md20100c]

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

AMORI, Laura;BRUNO, Agostino;CAMPANINI, Barbara;FELICI, Paolo;MOZZARELLI, Andrea;COSTANTINO, Gabriele
2012-01-01

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 were 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, showed higher affinity than the most active synthetic pentapeptide. Thus, in this communication we report the first example of potent 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. Noteworthy, the novel, small-sized, non-peptidic inhibitors retain the structural motifs of the bulky peptides, which are relevant for the enzyme inhibition.
Design and synthesis of trans-2-substituted-cyclopropane-1-carboxylic acids as the first non-natural small molecule inhibitors of O-acetylserine sulfhydrylase / Amori, Laura; S., Katkevica; Bruno, Agostino; Campanini, Barbara; Felici, Paolo; Mozzarelli, Andrea; Costantino, Gabriele. - In: MEDCHEMCOMM. - ISSN 2040-2503. - 3:(2012), pp. 1111-1116. [10.1039/c2md20100c]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2509244
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 35
  • ???jsp.display-item.citation.isi??? 34
social impact