Small Molecule Allosteric Modulators of Phosphodiesterase 4
Small Molecule Allosteric Modulators of Phosphodiesterase 4
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DOI：
10.1007/978-3-642-17969-3_7
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发表时间：
2011-01-01
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影响因子：
--
通讯作者：
Stewart, Lance J.
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文献类型：
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作者：
Gurney, Mark E.;Burgin, Alex B.;Stewart, Lance J.
磷酸二酯酶4（PDE 4）抑制剂已在人体临床试验中显示出获益，但剂量受到耐受性的限制，特别是因为呕吐。PDE 4催化单元与其调节结构域以及结合的抑制剂的新型共晶结构揭示了三种不同的PDE 4构象异构体，其可用于设计新型治疗剂。第一个是开放型构象异构体，它已用于竞争性PDE 4抑制剂的传统设计方法中。第二种是不对称二聚体，其中来自一个单体的UCR 2调节螺旋以闭合构象置于PDE 4二聚体中相对的活性位点上（反式加帽）。抑制剂一次只能封闭一个活性位点，结果是利用该构象异构体的化合物仅部分抑制PDE 4酶活性，同时在细胞和体内模型中保留效力。通过对PDE 4抑制的幅度设置固有上限，此类化合物可以更好地维持cAMP微域中信号传导的空间和时间模式，从而提高耐受性。第三种是对称的PDE 4构象异构体，其中来自催化单元的C-末端部分的螺旋封端两个活性位点（顺式封端）。我们建议，PDE 4活性的双门控可以通过辅助蛋白进一步微调，辅助蛋白识别PDE 4调节螺旋的开放或闭合构象。
Phosphodiesterase 4 (PDE4) inhibitors have shown benefit in human clinical trials but dosing is limited by tolerability, particularly because of emesis. Novel cocrystal structures of PDE4 catalytic units with their regulatory domains together with bound inhibitors have revealed three different PDE4 conformers that can be exploited in the design of novel therapeutic agents. The first is an open conformer, which has been employed in the traditional approach to the design of competitive PDE4 inhibitors. The second is an asymmetric dimer in which a UCR2 regulatory helix from one monomer is placed in a closed conformation over the opposite active site in the PDE4 dimer (trans-capping). Only one active site can be closed by an inhibitor at a time with the consequence that compounds exploiting this conformer only partially inhibit PDE4 enzymatic activity while retaining potency in cellular and in vivo models. By placing an intrinsic ceiling on the magnitude of PDE4 inhibition, such compounds may better maintain spatial and temporal patterning of signaling in cAMP microdomains with consequent improved tolerability. The third is a symmetric PDE4 conformer in which helices from the C-terminal portion of the catalytic unit cap both active sites (cis-capping). We propose that dual-gating of PDE4 activity may be further fine tuned by accessory proteins that recognize open or closed conformers of PDE4 regulatory helices.