Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS)., a highly conserved pyridoxal S'-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of "moonlighting" activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design) synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations.

Rational Design, Synthesis and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella Typhimurium O-Acetylserine Sulfhydrylase / PIERONI, Marco; ANNUNZIATO, Giannamaria; BEATO, Claudia; Wouters, R.; BENONI, Roberto; CAMPANINI, Barbara; PERTINHEZ, Thelma; BETTATI, Stefano; MOZZARELLI, Andrea; COSTANTINO, Gabriele. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 59:6(2016), pp. 2567-2578. [10.1021/acs.jmedchem.5b01775]

Rational Design, Synthesis and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella Typhimurium O-Acetylserine Sulfhydrylase

PIERONI, Marco;ANNUNZIATO, Giannamaria;BEATO, Claudia;BENONI, Roberto;CAMPANINI, Barbara
;
PERTINHEZ, Thelma;BETTATI, Stefano;MOZZARELLI, Andrea;COSTANTINO, Gabriele
2016

Abstract

Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS)., a highly conserved pyridoxal S'-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of "moonlighting" activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design) synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations.
Rational Design, Synthesis and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella Typhimurium O-Acetylserine Sulfhydrylase / PIERONI, Marco; ANNUNZIATO, Giannamaria; BEATO, Claudia; Wouters, R.; BENONI, Roberto; CAMPANINI, Barbara; PERTINHEZ, Thelma; BETTATI, Stefano; MOZZARELLI, Andrea; COSTANTINO, Gabriele. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 1520-4804. - 59:6(2016), pp. 2567-2578. [10.1021/acs.jmedchem.5b01775]
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2806191
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