Junliu Huang, Zexuan Lin, Jishun Yang, Huining Tang, Yang Yang, Yi Tang, Feixian Luo, Wenshu Wang, Xiaojie Cui
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引用次数: 0
Abstract
The human telomeric repeat CCCTAA has been reported to form a higher-order structure called an intercalated motif (i-motif) that plays important roles in telomere function and telomerase activity regulation, and small molecule ligands targeting human telomeric i-motif (hTelo-iM) is a promising therapeutic strategy for cancer treatment, yet the i-motif folding pattern of long CCCTAA repeats and the hTelo-iM ligand screening have not been studied extensively. In this study, we systematically investigated the i-motif structures formed by four and eight telomeric C-rich repeats d(CCCTAA)4 (hTeloC-24mer) and d(CCCTAA)8 (hTeloC-48mer) under varied conditions and found that the long hTeloC-48mer probably forms unstacked tandem i-motif consisting of two hTeloC-24mer i-motif monomers under near physiological conditions. Moreover, natural bisbenzylisoquinoline (BBI) alkaloids, isofangchinoline, fangchinoline, cepharanthine, and tetrandrine, were screened from 33 natural small molecules to effectively disrupt and destabilize the hTelo-iM structures mainly through major groove hydrogen bonding and van der Waals interactions. Further, telomerase repeated amplification protocol (TRAP) assay suggested that the selected BBI alkaloids can inhibit the telomere extension by telomerase. These findings provide a theoretical basis for further telomere structure research as well as a novel class of natural small molecule compounds regulating the hTelo-iM structure and telomerase activity, which may contribute to the anticancer drug design and strategy development taking the hTelo-iM as a target.
期刊介绍:
ACS Chemical Biology provides an international forum for the rapid communication of research that broadly embraces the interface between chemistry and biology.
The journal also serves as a forum to facilitate the communication between biologists and chemists that will translate into new research opportunities and discoveries. Results will be published in which molecular reasoning has been used to probe questions through in vitro investigations, cell biological methods, or organismic studies.
We welcome mechanistic studies on proteins, nucleic acids, sugars, lipids, and nonbiological polymers. The journal serves a large scientific community, exploring cellular function from both chemical and biological perspectives. It is understood that submitted work is based upon original results and has not been published previously.