Berger Joel P, SinhaRoy Ranabir, Pocai Alessandro, Kelly Theresa M, Scapin Giovanna, Gao Ying-Duo, Pryor Kelly Ann D, Wu Joseph K, Eiermann George J, Xu Shiyao S, Zhang Xiaoping, Tatosian Daniel A, Weber Ann E, Thornberry Nancy A, Carr Richard D
Merck& Co., Inc. Kenilworth NJ USA.
Present address: Takeda Pharmaceuticals International, Inc. Cambridge MA USA.
Endocrinol Diabetes Metab. 2017 Nov 24;1(1):e00002. doi: 10.1002/edm2.2. eCollection 2018 Jan.
Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity.
We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy.
Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice.
The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.
自2006年以来，二肽基肽酶-4（DPP-4）抑制剂已成为治疗2型糖尿病的既定疗法。尽管DPP-4抑制剂类成员具有共同的作用机制，但它们在化学结构上存在很大差异，这就引发了一个问题，即结构差异是否会导致不同的酶抑制作用和降血糖活性。
我们比较了最常用抑制剂的结合特性，并研究了它们在酶水平的抑制效力与其急性降糖疗效之间的关系。
首先，结合已发表的晶体结构和内部数据，我们证明所有评估的DPP-4抑制剂所利用的结合位点与神经肽Y所使用的相同，支持了DPP-4抑制剂能够竞争性抑制该酶内源性底物的假说。其次，我们确定DPP-4的酶裂隙是一个相对较大的腔，它具有构象灵活性以容纳结构多样的抑制剂分子。最后，我们发现对于所有抑制剂，无论其化学结构如何，血浆DPP-4酶活性的抑制与小鼠急性血浆葡萄糖降低直接相关。
不同的DPP-4抑制剂所利用的共同结合位点能够对内源性DPP-4底物的裂解进行类似的竞争性抑制。此外，尽管DPP-4抑制剂之间存在化学多样性和一系列结合效力，但在所研究的每一类抑制剂中，小鼠血浆中的酶抑制与血糖降低之间都存在明显的直接关系。
