Journal
NUCLEIC ACIDS RESEARCH
Volume 48, Issue 9, Pages 4627-4642Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkaa186
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Funding
- Bill and Melinda Gates Foundation [GCE grant ] [OPP1035881, OPP1097238]
- European Research Council [ERC Consolidator grant] [615879]
- Bill and Melinda Gates Foundation
- European Research Council (ERC) [615879] Funding Source: European Research Council (ERC)
- Bill and Melinda Gates Foundation [OPP1035881] Funding Source: Bill and Melinda Gates Foundation
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Targeting of G-quadruplexes, non-canonical conformations that form in G-rich regions of nucleic acids, has been proposed as a novel therapeutic strategy toward several diseases, including cancer and infections. The unavailability of highly selective molecules targeting a G-quadruplex of choice has hampered relevant applications. Herein, we describe a novel approach, based on naphthalene diimide (NDI)-peptide nucleic acid (PNA) conjugates, taking advantage of the cooperative interaction of the NDI with the G-quadruplex structure and hybridization of the PNA with the flanking region upstream or downstream the targeted G-quadruplex. By biophysical and biomolecular assays, we show that the NDI-PNA conjugates are able to specifically recognize the G-quadruplex of choice within the HIV-1 LTR region, consisting of overlapping and therefore mutually exclusive G-quadruplexes. Additionally, the conjugates can induce and stabilize the least populated G-quadruplex at the expenses of the more stable ones. The general and straightforward design and synthesis, which readily apply to any G4 target of choice, together with both the red-fluorescent emission and the possibility to introduce cellular localization signals, make the novel conjugates available to selectively control G-quadruplex folding over a wide range of applications.
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