Dutta, Debasish ; Debnath, Manish ; Müller, Diana ; Paul, Rakesh ; Das, Tania ; Bessi, Irene ; Schwalbe, Harald ; Dash, Jyotirmayee (2018) Cell penetrating thiazole peptides inhibit c-MYC expression via site-specific targeting of c-MYC G-quadruplex Nucleic Acids Research, 46 (11). pp. 5355-5365. ISSN 0305-1048
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Official URL: http://doi.org/10.1093/nar/gky385
Related URL: http://dx.doi.org/10.1093/nar/gky385
Abstract
The structural differences among different G-quadruplexes provide an opportunity for site-specific targeting of a particular G-quadruplex structure. However, majority of G-quadruplex ligands described thus far show little selectivity among different G-quadruplexes. In this work, we delineate the design and synthesis of a crescent-shaped thiazole peptide that preferentially stabilizes c-MYC quadruplex over other promoter G-quadruplexes and inhibits c-MYC oncogene expression. Biophysical analysis such as Förster resonance energy transfer (FRET) melting and fluorescence spectroscopy show that the thiazole peptide TH3 can selectively interact with the c-MYC G-quadruplex over other investigated G-quadruplexes and duplex DNA. NMR spectroscopy reveals that peptide TH3 binds to the terminal G-quartets and capping regions present in the 5′- and 3′-ends of c-MYC G-quadruplex with a 2:1 stoichiometry; whereas structurally related distamycin A is reported to interact with quadruplex structures via groove binding and end stacking modes with 4:1 stoichiometry. Importantly, qRT-PCR, western blot and dual luciferase reporter assay show that TH3 downregulates c-MYC expression by stabilizing the c-MYC G-quadruplex in cancer cells. Moreover, TH3 localizes within the nucleus of cancer cells and exhibits antiproliferative activities by inducing S phase cell cycle arrest and apoptosis.
Item Type: | Article |
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Source: | Copyright of this article belongs to National Library of Medicine. |
ID Code: | 126647 |
Deposited On: | 17 Oct 2022 05:44 |
Last Modified: | 17 Oct 2022 05:44 |
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