Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4).
Chemical informatics uncovers a new role for moexipril as a novel inhibitor of cAMP phosphodiesterase-4 (PDE4).
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DOI：
10.1016/j.bcp.2013.02.026
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发表时间：
2013-05-01
影响因子：
5.8
通讯作者：
Baillie, George S.
中科院分区：
文献类型：
--
作者：
Cameron, Ryan T.;Coleman, Ryan G.;Day, Jon P.;Yalla, Krishna C.;Houslay, Miles D.;Adams, David R.;Shoichet, Brian K.;Baillie, George S.
关键词：
PDE4是已知的11个环核苷酸磷酸二酯酶家族之一，在介导重要的环核苷酸第二信使环3′5′腺苷单磷酸（cAMP）的水解降解中起关键作用。PDE4抑制剂已知具有抗炎特性，但其在临床中的应用一直受到机制相关副作用的阻碍，这些副作用限制了最大耐受剂量。为了开始开发耐受性更好的PDE4抑制剂，我们调查了现有已批准的PDE4抑制活性药物。为此，我们利用高通量计算方法鉴定了moexipril（一种耐受性良好且安全的血管紧张素转换酶（ACE）抑制剂）作为PDE4抑制剂。实验表明，莫西普利和两种结构相关的类似物在微摩尔范围内抑制PDE4活性。利用由cAMP激活的1型交换蛋白EPAC1的核苷酸结合域构建的基于fret的生物传感器，我们证明了莫西普利显著增强了福斯克林提高细胞内cAMP水平的能力。最后，我们证明了莫西普利的PDE4抑制作用在功能上能够诱导cAMP依赖性蛋白激酶a对小热休克蛋白Hsp20的磷酸化。我们的数据表明莫西普利是一种真正的PDE4抑制剂，可能为开发具有改善治疗窗口的新型PDE4抑制剂提供起点。
PDE4 is one of eleven known cyclic nucleotide phosphodiesterase families and plays a pivotal role in mediating hydrolytic degradation of the important cyclic nucleotide second messenger, cyclic 3′5′ adenosine monophosphate (cAMP). PDE4 inhibitors are known to have anti-inflammatory properties, but their use in the clinic has been hampered by mechanism-associated side effects that limit maximally tolerated doses. In an attempt to initiate the development of better-tolerated PDE4 inhibitors we have surveyed existing approved drugs for PDE4-inhibitory activity. With this objective, we utilised a high-throughput computational approach that identified moexipril, a well tolerated and safe angiotensin-converting enzyme (ACE) inhibitor, as a PDE4 inhibitor. Experimentally we showed that moexipril and two structurally related analogues acted in the micro molar range to inhibit PDE4 activity. Employing a FRET-based biosensor constructed from the nucleotide binding domain of the type 1 exchange protein activated by cAMP, EPAC1, we demonstrated that moexipril markedly potentiated the ability of forskolin to increase intracellular cAMP levels. Finally, we demonstrated that the PDE4 inhibitory effect of moexipril is functionally able to induce phosphorylation of the small heat shock protein, Hsp20, by cAMP dependent protein kinase A. Our data suggest that moexipril is a bona fide PDE4 inhibitor that may provide the starting point for development of novel PDE4 inhibitors with an improved therapeutic window.
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