Andrei Sebastian A, Sijbesma Eline, Hann Michael, Davis Jeremy, O'Mahony Gavin, Perry Matthew W D, Karawajczyk Anna, Eickhoff Jan, Brunsveld Luc, Doveston Richard G, Milroy Lech-Gustav, Ottmann Christian
a Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems , Eindhoven University of Technology , Eindhoven , The Netherlands.
b Platform Technology and Science, Medicines Research Centre , GlaxoSmithKline R&D , Stevenage , UK.
Expert Opin Drug Discov. 2017 Sep;12(9):925-940. doi: 10.1080/17460441.2017.1346608. Epub 2017 Jul 11.
PPIs are involved in every disease and specific modulation of these PPIs with small molecules would significantly improve our prospects of developing therapeutic agents. Both industry and academia have engaged in the identification and use of PPI inhibitors. However in comparison, the opposite strategy of employing small-molecule stabilizers of PPIs is underrepresented in drug discovery. Areas covered: PPI stabilization has not been exploited in a systematic manner. Rather, this concept validated by a number of therapeutically used natural products like rapamycin and paclitaxel has been shown retrospectively to be the basis of the activity of synthetic molecules originating from drug discovery projects among them lenalidomide and tafamidis. Here, the authors cover the growing number of synthetic small-molecule PPI stabilizers to advocate for a stronger consideration of this as a drug discovery approach. Expert opinion: Both the natural products and the growing number of synthetic molecules show that PPI stabilization is a viable strategy for drug discovery. There is certainly a significant challenge to adapt compound libraries, screening techniques and downstream methodologies to identify, characterize and optimize PPI stabilizers, but the examples of molecules reviewed here in our opinion justify these efforts.
质子泵抑制剂（PPIs）与各种疾病相关，利用小分子对这些PPIs进行特异性调控将显著改善我们开发治疗药物的前景。制药行业和学术界都致力于质子泵抑制剂抑制剂的识别与应用。然而，相比之下，在药物研发中，采用质子泵抑制剂小分子稳定剂的相反策略却较少受到关注。涵盖领域：质子泵抑制剂的稳定作用尚未得到系统开发。确切地说，雷帕霉素和紫杉醇等多种治疗用天然产物所验证的这一概念，已被追溯证明是来那度胺和他氟米特等药物研发项目中合成分子活性的基础。在此，作者介绍了越来越多的合成小分子质子泵抑制剂稳定剂，以倡导更深入地将其作为一种药物研发方法加以考虑。专家观点：天然产物和越来越多的合成分子均表明，质子泵抑制剂稳定作用是一种可行的药物研发策略。要调整化合物库、筛选技术和下游方法以识别、表征和优化质子泵抑制剂稳定剂，无疑面临重大挑战，但我们认为，本文所综述的分子实例证明了这些努力的合理性。
