Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction,ACS Medicinal Chemistry Letters

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Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-04-25 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00152
Xia Chen ₁ , Liu Liu , Yong Chen ₂ , Yuting Yang , Chao-Yie Yang , Tianyue Guo ₁ , Ming Lei _{3,

4} , Haiying Sun ₁ , Shaomeng Wang

Affiliation

Telomeric repeat binding factor 2 (TRF2) is a telomere-associated protein that plays an important role in the formation of the 3′ single strand DNA overhang and the “T loop”, two structures critical for the stability of the telomeres. Apollo is a 5′-exonuclease recruited by TRF2 to the telomere and contributes to the formation of the 3′ single strand DNA overhang. Knocking down of Apollo can induce DNA damage response similar to that caused by the knocking down of TRF2. In this Letter, we report the design and synthesis of a class of cyclic peptidic mimetics of the TRFH binding motif of Apollo (Apollo_TBM). We found conformational control of the C terminal residues of Apollo_TBM can effectively improve the binding affinity. We have obtained a crystal structure of a cyclic peptidic Apollo peptide mimetic (34) complexed with TRF2, which provides valuable guidance to the future design of TRF2 inhibitors.

中文翻译：

靶向端粒重复结合因子2（TRF2）和阿波罗相互作用的阿波罗肽的环肽模拟物

端粒重复结合因子2（TRF2）是一种端粒相关蛋白，在3'单链DNA突出端和“ T环”（端粒稳定性至关重要的两个结构）的形成中起着重要作用。阿波罗是由TRF2募集到端粒的5'核酸外切酶，并有助于3'单链DNA突出端的形成。敲除阿波罗可以诱导类似于TRF2敲除引起的DNA损伤反应。在这封信中，我们报告了阿波罗TRFH结合基序（Apollo _TBM）的一类环状肽模拟物的设计和合成。我们发现阿波罗_TBM C末端残基的构象控制可以有效提高结合亲和力。我们已经获得了与TRF2络合的环状肽Apollo肽模拟物（34）的晶体结构，这为TRF2抑制剂的未来设计提供了有价值的指导。

更新日期：2018-04-25

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