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

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

doi:10.1021/acsmedchemlett.8b00152

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

Journal Article · Wed Apr 25 00:00:00 EDT 2018 · ACS Medicinal Chemistry Letters

DOI:https://doi.org/10.1021/acsmedchemlett.8b00152· OSTI ID:1544872

Chen, Xia ^[1]; Liu, Liu ^[2]; Chen, Yong ^[3]; Yang, Yuting ^[2]; ^[2]; Guo, Tianyue ^[1]; Lei, Ming ^[4]; ^[1]; ^[2]

China Pharmaceutical Univ., Nanjing (China)
Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Chinese Academy of Sciences, Shanghai (China)
Shanghai Jiaotong Univ. School of Medicine, (China); Shanghai Inst. of Precision Medicine (China)

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. Further, 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.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Natural Science Foundation of China (NSFC)

OSTI ID:: 1544872

Journal Information:: ACS Medicinal Chemistry Letters, Journal Name: ACS Medicinal Chemistry Letters Journal Issue: 5 Vol. 9; ISSN 1948-5875

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
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TRF2
Telomere
peptidic mimetics
protein−protein interaction

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

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References (22)

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