Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production

被引：20

作者：

Corvino, Angela ^{[1
,5
]}

Severino, Beatrice ^{[1
]}

Fiorino, Ferdinando ^{[1
]}

Frecentese, Francesco ^{[1
]}

Magli, Elisa ^{[1
]}

Perissutti, Elisa ^{[1
]}

Santagada, Vincenzo ^{[1
]}

Bucci, Mariarosaria ^{[1
]}

Cirino, Giuseppe ^{[1
]}

Kelly, Geoff ^{[2
]}

Servillo, Luigi ^{[3
]}

Popowicz, Grzegorz ^{[4
]}

Pastore, Annalisa ^{[5
]}

Caliendo, Giuseppe ^{[1
]}

机构：

[1] Univ Naples Federico II, Dept Pharm, Via D Montesano 49, I-80131 Naples, Italy

[2] NIMR, MRC, Biomed NMR Ctr, London NW7 1AA, England

[3] Univ Naples 2, Dept Biochem Biophys & Gen Pathol, Caserta Ce, Italy

[4] Tech Univ Munich, Garching Campus, Munich, Germany

[5] Kings Coll London, Wohl Inst, Dept Neurosci, Denmark Hill Campus, London SE5, England

来源：

SCIENTIFIC REPORTS | 2016年 / 6卷

关键词：

BETA-SYNTHASE; H2S;

D O I：

10.1038/srep34398

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Hydrogen sulfide is an essential catabolite that intervenes in the pathophysiology of several diseases from hypertension to stroke, diabetes and pancreatitis. It is endogenously synthesized mainly by two pyridoxal-5'-phosphate-dependent enzymes involved in L-cysteine metabolism: cystathionine-beta-synthase (CBS) and cystathionine-gamma-lyase (CSE). Research in this field is currently impaired by the lack of pharmacological tools such as selective enzymatic inhibitors that could target specifically only one of these pathways. We used a novel approach based on a hybrid method that includes drug design, synthetic biology, metabolomics and pharmacological assays to rationally design a new inhibitor selective for the CSE enzyme. The identification of this compound opens new frontiers towards a better understanding of the role of CSE over CBS in the pathophysiology of diseases where a role for the H2S pathway has been proposed and the development of new lead compounds that could target the CSE enzyme.

引用

页数：11

共 26 条

[1] Selectivity of commonly used pharmacological inhibitors for cystathionine synthase (CBS) and cystathionine lyase (CSE) [J].