N-terminal modified cyclopeptidic mimetics of ApolloTBM as inhibitors of TRF2

Xia Chen; Yao Dong; Tianyue Guo; Chao-Yie Yang; Yong Chen; Haiying Sun

doi:10.1016/j.bmcl.2020.127401

N-terminal modified cyclopeptidic mimetics of Apollo_TBM as inhibitors of TRF2

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127401. doi: 10.1016/j.bmcl.2020.127401. Epub 2020 Jul 13.

Authors

Xia Chen¹, Yao Dong¹, Tianyue Guo¹, Chao-Yie Yang², Yong Chen³, Haiying Sun⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China.
² Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
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, Shanghai 201210, China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China. Electronic address: haiyings1969@cpu.edu.cn.

PMID: 32871539
DOI: 10.1016/j.bmcl.2020.127401

Abstract

Telomeric repeat binding factor 2 (TRF2) plays an important role in protecting telomeres from being recognized as DNA breaks. TRF2 performs its telomere protecting functions partially by recruiting a number of accessory proteins to telomeres through its TRF homology (TFRH) domain. Identification of small molecular compounds which can bind to the TRFH domain of TRF2 and block the interactions between TRF2 and its associated proteins is crucial for elucidating the molecular mechanisms of these protein-protein interactions. Using a previously identified peptidic mimetic of Apollo_TBM as a lead compound, we designed and synthesized a series of novel TRF2 inhibitors by non-peptidic modifications of the N-terminal residues. These compounds can maintain the binding affinities to TRF2 but have much reduced peptidic characteristics compared to the lead compound.

Keywords: Peptidic mimetics; Protein-protein interaction; TRF2; Telomere.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Dose-Response Relationship, Drug
Humans
Models, Molecular
Molecular Structure
Peptides, Cyclic / chemical synthesis
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Structure-Activity Relationship
Telomeric Repeat Binding Protein 2 / antagonists & inhibitors*

Substances

Peptides, Cyclic
TERF2 protein, human
Telomeric Repeat Binding Protein 2