当前位置: X-MOL 学术Eur. J. Med. Chem. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Targeting different binding sites in the CFTR structures allows to synergistically potentiate channel activity.
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2020-02-09 , DOI: 10.1016/j.ejmech.2020.112116
Lionel Froux 1 , Ahmad Elbahnsi 2 , Benjamin Boucherle 3 , Arnaud Billet 1 , Nesrine Baatallah 4 , Brice Hoffmann 2 , Julien Alliot 3 , Renaud Zelli 3 , Wael Zeinyeh 3 , Romain Haudecoeur 3 , Benoit Chevalier 4 , Antoine Fortuné 3 , Sandra Mirval 1 , Christophe Simard 1 , Pierre Lehn 5 , Jean-Paul Mornon 2 , Alexandre Hinzpeter 4 , Frédéric Becq 1 , Isabelle Callebaut 2 , Jean-Luc Décout 3
Affiliation  

Recent evidence shows that combination of correctors and potentiators, such as the drug ivacaftor (VX-770), can significantly restore the functional expression of mutated Cystic Fibrosis Transmembrane conductance Regulator (CFTR), an anion channel which is mutated in cystic fibrosis (CF). The success of these combinatorial therapies highlights the necessity of identifying a broad panel of specific binding mode modulators, occupying several distinct binding sites at structural level. Here, we identified two small molecules, SBC040 and SBC219, which are two efficient cAMP-independent potentiators, acting at low concentration of forskolin with EC50 close to 1 μM and in a synergic way with the drug VX-770 on several CFTR mutants of classes II and III. Molecular dynamics simulations suggested potential SBC binding sites at the vicinity of ATP-binding sites, distinct from those currently proposed for VX-770, outlining SBC molecules as members of a new family of potentiators.

中文翻译:

靶向CFTR结构中的不同结合位点可以协同增强通道活性。

最近的证据表明,校正剂和增强剂(例如药物ivacaftor(VX-770))的组合可以显着恢复突变的囊性纤维化跨膜电导调节剂(CFTR)的功能表达,CFTR是在囊性纤维化(CF)中突变的阴离子通道。 。这些组合疗法的成功凸显了鉴定广泛的特异性结合模式调节剂的必要性,这些调节剂在结构水平上占据了几个不同的结合位点。在这里,我们确定了两个小分子SBC040和SBC219,这两个是独立于cAMP的有效增强剂,它们在低浓度的Forskolin(EC50接近1μM)下以协同作用与VX-770协同作用于几种CFTR突变体上二和三。
更新日期:2020-02-10
down
wechat
bug