Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction

Xia Chen; Liu Liu; Yong Chen; Yuting Yang; Chao-Yie Yang; Tianyue Guo; Ming Lei; Haiying Sun; Shaomeng Wang

doi:10.1021/acsmedchemlett.8b00152

Cyclic Peptidic Mimetics of Apollo Peptides Targeting Telomeric Repeat Binding Factor 2 (TRF2) and Apollo Interaction

ACS Med Chem Lett. 2018 Apr 25;9(5):507-511. doi: 10.1021/acsmedchemlett.8b00152. eCollection 2018 May 10.

Authors

Xia Chen¹, Liu Liu², Yong Chen³, Yuting Yang², Chao-Yie Yang², Tianyue Guo¹, Ming Lei^{4

5}, Haiying Sun¹, Shaomeng Wang²

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Department of Medicinal Chemistry, Department of Internal Medicine, Comprehensive Cancer Center, and Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan 48109, United States.
³ State Key Laboratory of Molecular Biology, National Center for Protein Science, Shanghai Science Research Center, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 333 Haike Road, Shanghai 201210, China.
⁴ Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, 639 Zhizaoju Lu, Shanghai 200011, China.
⁵ Shanghai Institute of Precision Medicine, Shanghai 200125, China.

Abstract

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.