Gurney Mark E, Burgin Alex B, Magnusson Olafur T, Stewart Lance J
Tetra Discovery Partners, Grand Rapids, MI, USA.
Handb Exp Pharmacol. 2011(204):167-92. doi: 10.1007/978-3-642-17969-3_7.
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.
磷酸二酯酶4（PDE4）抑制剂在人体临床试验中已显示出疗效，但给药剂量受耐受性限制，尤其是因为呕吐。PDE4催化单元与其调节结构域以及结合抑制剂的新型共晶体结构揭示了三种不同的PDE4构象，可用于新型治疗药物的设计。第一种是开放构象，已被用于传统的竞争性PDE4抑制剂设计方法中。第二种是不对称二聚体，其中一个单体的UCR2调节螺旋以封闭构象置于PDE4二聚体中相对的活性位点上方（反式封端）。一次只有一个活性位点能被抑制剂封闭，结果是利用这种构象的化合物只能部分抑制PDE4酶活性，同时在细胞和体内模型中保持效力。通过对PDE4抑制程度设置内在上限，此类化合物可能更好地维持cAMP微区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PDE4构象，其中催化单元C末端部分的螺旋封闭两个活性位点（顺式封端）。我们提出，PDE4活性的双重门控可能会通过识别PDE4调节螺旋开放或封闭构象的辅助蛋白进一步微调。
