The Use of a Peptidic Scaffold for the Formation of Stable Guanine Tetrads: Control of a H‐bonded Pattern in Water

Abstract

International audienc

Multitasking Water‐Soluble Synthetic G‐Quartets: From Preferential RNA–Quadruplex Interaction to Biocatalytic Activity

“…An important step was taken with the synthesis of water‐soluble TASQ. The water solubility is mostly imparted by the nature of the template that is used to assemble the G‐tetramer: a DOTA‐like polyazamacrocycle (DOTASQ, for DOTA‐templated synthetic G‐quartet, with DOTA: 1,4,7,10‐tetraazacyclododecane‐ N , N ′, N ′′, N ′′′‐tetraacetic acid, Figure 1 A),26 a water‐soluble calixarene (Figure 1 B),27 a macrocyclodecapeptide (RAFT‐G4, for regioselectively addressable functionalized template, Figure 1 C),28 and more recently a porphyrin ring (PorphySQ, Figure 1 D). 29 This water‐solubility, along with their quite unique structural features (schematically represented in Figure 1 A), that is, their ability to adopt alternatively an “open” (in which the guanines are independent) and a “closed” conformation (in which the guanines are involved in the SQ), have opened an avenue to biologically directed applications: DOTASQ has been, for example, evaluated as a G‐quadruplex ligand (which interacts with its DNA target according to a “like likes like” process driven by the nature‐inspired assembly of two G‐quartets, one from the TASQ, the other one from the G‐quadruplex),26 as a pre‐catalyst for peroxidase‐mimicking oxidative reactions30 (alongside RAFT‐G4,31 in a DNAzyme‐inspired manner, this pseudo‐enzymatic activity was consequently termed TASQzyme), and as enhancing agents for G‐quadruplex‐based DNAzyme processes 32.…”

Prefolded Synthetic G‐Quartets Display Enhanced Bioinspired Properties

“…The presence of as ingle peak at d = 10.98 ppm in the 1 HNMR spectra recorded in water ( Figure 2A)c orresponds to the imino protons of guanine moieties protected from solvent exchange:t his implies their involvement in Hoogsteentype H-bonds, thusc onfirming the existence of the intramolecular G-quartetf old of TASQ 2 alone in solution.M oreover,2 D-NOESY NMR analysis ( Figure 2B)r eveals as trong NOE crosspeak between H8 protons of the guanosine nucleobases (at d = 7.51 and 7.47 ppm) [18] and their own H1' sugar proton( at d = 5.73 ppm), thus implying a syn conformation along the glycosidic bond, [19] in good agreement with the formation of guanine quartet. [10,12] The 2D-DOSY analysis confirms the existence of as ingle population of TASQ 2,w hereas TASQ 1 clearly exhibited two populations under similar conditions. [10,12] The 2D-DOSY analysis confirms the existence of as ingle population of TASQ 2,w hereas TASQ 1 clearly exhibited two populations under similar conditions.…”

“…TASQ 1, [10] peptide 3, [17] and 5'-azido-guanosine [16] were prepared as previously described. Protected amino acids were obtained from Activotec and Novabiochem.…”

“…The former makes them biomimetic quadruplex ligands, asserting that the best ligands for quadruplexes should be as ingle quartet throughs elf-associationo fs ynthetic (ligand) and native (quadruplex) quartets, according to a" like-likes-like"a pproach. We thus reasoned that ap refolded intramolecular quartet would undoubtedly favor and promote their activity and consequentlyw er eport herein on an ew series of TASQ that display stable G-quartet folds even alone in solution.T oa ssess if the preformation of the intramolecular quartet could influence the interaction with externalb inding agents (porphyrins, quadruplexes), we decidedt os ynthesize and comparet he properties of TASQ 1 and 2.T hey are both constructed by the attachment of four guanosines via their 5'-hydroxyl ends to aw ater-soluble cyclodecapeptide template (RAFT,F igure 1) [10] through triazole linkages. hemin) that become catalytically competento nce nestled in ap rotein-like bindingc avity (i.e.…”

Tri‐G‐Quadruplex: Controlled Assembly of a G‐Quadruplex Structure from Three G‐Rich Strands

“…Alternative templated strategies have been proposed to pre-organize the G-units for the formation of Gquartets or G-quadruplexes. [22][23][24][25][26][27] The duplex approach we used herein is simple and versatile; it relies on commercially available products and could be easily transposed to different sequences. In fact, we found that linker duplexes as short as six base pairs are sufficient for guiding the tri-G-quadruplex formation ( Figure S5).…”