Use of a Fission Yeast Platform to Identify and Characterize Small Molecule PDE Inhibitors.
Use of a Fission Yeast Platform to Identify and Characterize Small Molecule PDE Inhibitors.
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DOI：
10.3389/fphar.2021.833156
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发表时间：
2021
影响因子：
5.6
通讯作者：
Hoffman CS
中科院分区：
文献类型：
--
作者：
Hoffman CS
环核苷酸磷酸二酯酶(PDE)已被证明是高选择性和强效药物开发的靶点。哺乳动物基因组有21个基因，其产物从药理上分为11个家族；然而，病原体的相关基因与哺乳动物的同源物有很大的差异，因此这些酶的PDE抑制剂可以用于治疗寄生虫感染，而不作用于相关的人类PDE。我们已经开发了一个在裂殖酵母中表达克隆的PDE的平台，允许廉价但强大的筛选具有细胞渗透性的小分子抑制剂。当在细胞培养中测试时，这些化合物通常显示出预期的生物活性，包括PDE4和PDE7抑制剂的抗炎特性。作为研究PDE-抑制剂相互作用的一种方式，S.pombe的遗传柔韧性也允许分子遗传筛选来识别目标PDE基因的突变，这些突变赋予了对这些抑制剂的一些抗性。这种筛选方法很容易被学术实验室使用，因为它不需要纯化大量的目标蛋白。这允许发现和分析PDE抑制剂来治疗炎症或靶标的抑制剂，例如病原体PDE，而制药公司可能没有足够的财务动机来使用更传统的基于酶的体外筛选方法来识别选择性PDE抑制剂。
Cyclic nucleotide phosphodiesterases (PDEs) have been proven to be targets for which highly selective and potent drugs can be developed. Mammalian genomes possess 21 genes whose products are pharmacologically grouped into 11 families; however related genes from pathogenic organisms display sufficient divergence from the mammalian homologs such that PDE inhibitors to these enzymes could be used to treat parasitic infections without acting on the related human PDEs. We have developed a platform for expressing cloned PDEs in the fission yeast Schizosaccharomyces pombe, allowing for inexpensive, but robust screening for small molecule inhibitors that are cell permeable. Such compounds typically display the expected biological activity when tested in cell culture, including anti-inflammatory properties for PDE4 and PDE7 inhibitors. The genetic pliability of S. pombe also allows for molecular genetic screens to identify mutations in target PDE genes that confer some resistance to these inhibitors as a way of investigating the PDE-inhibitor interaction. This screening method is readily accessible to academic laboratories as it does not require the purification of large quantities of a target protein. This allows for the discovery and profiling of PDE inhibitors to treat inflammation or of inhibitors of targets such as pathogen PDEs for which there may not be a sufficient financial motivation for pharmaceutical companies to identify selective PDE inhibitors using more traditional in vitro enzyme-based screening methods.
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影响因子：
3.8
作者：
ANGEL, JB;SAGET, BM;ENDRES, S
通讯作者：
ENDRES, S
影响因子：
7.8
作者：
Hasson, Samuel A.;Inglese, James
通讯作者：
Inglese, James
影响因子：
64.5
作者：
ELION, EA;GRISAFI, PL;FINK, GR
通讯作者：
FINK, GR
影响因子：
3.9
作者：
de Medeiros, Ana Santos;Magee, Alexander;Hoffman, Charles S.
通讯作者：
Hoffman, Charles S.
DOI：
10.1007/978-3-642-17969-3_5
发表时间：
2011-01-01
期刊：
PHOSPHODIESTERASES AS DRUG TARGETS
影响因子：
--
作者：
Demirbas, Didem;Ceyhan, Ozge;Hoffman, Charles S.
通讯作者：
Hoffman, Charles S.