Manipulating DNA G‐Quadruplex Structures by Using Guanosine Analogues

Abstract

The ability to control the folding topology of DNA G‐quadruplexes allows for rational design of quadruplex‐based scaffolds for potential use in various therapeutic and technological applications. By exploiting the distinct conformational properties of some base‐ and sugar‐modified guanosine surrogates, conformational transitions can be induced through their judicious incorporation at specific sites in the quadruplex core. Changes may involve tetrad polarity inversions with conservation of the global fold or complete refolding to new topologies. Reliable predictions relating to low‐energy conformers formed upon specific chemical perturbations of the system and the rational design of modified sequences suffer from our still limited understanding of the subtle interplay of various favorable and unfavorable interactions within a particular quadruplex scaffold. However, aided by an increasing number of systematic substitution experiments and high‐resolution structures of modified quadruplex variants, critical interactions, in addition to glycosidic bond angle propensities, are starting to emerge as important contributors to modification‐driven quadruplex refolding.

Sugar Puckering Drives G‐Quadruplex Refolding: Implications for V‐Shaped Loops

“…Approaches for a versatile and rational G4 design are expected to heavily support many bio‐ and nanotechnological G4 applications. A powerful and efficient strategy for the directed manipulation of the topology for a given G4‐forming sequence involves the deliberate incorporation of G‐analogues . Here, the glycosidic torsion angle plays a major role as it is correlated with strand orientation and tetrad polarity.…”

“…A powerful and efficient strategy for the directed manipulation of the topology for a given G4-forming sequence involves the deliberate incorporation of G-analogues. [30] Here, the glycosidic torsion angle plays a major role as it is correlated with strand orientation and tetrad polarity. Apart from a complete disruption of the quadruplex fold, an anti to syn or syn to anti transition is necessarily accompanied by an inversion of either the tetrad polarity or the G-tract orientation.…”

Duplex‐Guided Refolding into Novel G‐Quadruplex (3+1) Hybrid Conformations

“…[1] Although rules have emerged that correlate sequences to the stability of particular G4 topological features, [2] reliable predictions of G4 conformations are challenging because of our still limited knowledge of the various interactions that determine G4 folding.D eliberately engineering specific folds will therefore not only provide an expanded collection of G-quadruplex scaffolds to be used for the increasing number of technological applications,f or example,a sa ptamers or parts of nanoarchitectures, [3,4] but will also contribute to ab etter understanding of the forces acting along the G4 folding pathway. [5] Thes sQ oligomer d(GCGTG 3 TCAG 3 TG 3 TG 3 CTCA) with 5'-a nd 3'-overhangs and one three-nucleotide (3-nt) as well as two 1-nt intervening sequences between its four G-tracts is based on at runcated variant of the guanine-rich strand of the nuclease hypersensitive element III 1 in the c-MYC promoter.T he latter has been shown to fold into av ery robust parallel G-quadruplex with three short pro-peller-type loops. [6] However,the 3-nt intervening sequence in ssQ is expected to also allow formation of al ateral loop to yield an ovel (3+ +1) hybrid topology with af irst lateral followed by two propeller loops ( Figure 1).…”

Duplex‐gesteuerte Umfaltung in neuartige G‐Quadruplex‐(3+1)‐ Hybridkonformationen

“…Ihre bemerkenswerte Strukturpolymorphie leitet sich vom Looptyp der G-Trakt-verbindenden Sequenzen, der relativen Orientierung der G-Trakte zueinander sowie von der Abfolge glykosidischer Konformationen entlang der G-Trakte ab. [5] Das Oligomer ssQ d(GCGTG 3 TCAG 3 TG 3 TG 3 CTCA) mit Überhängen am 5'-u nd 3'-Ende und einer Drei-Nukleotid (3-nt)-sowie zwei Ein-Nukleotid-Sequenzen zwischen den G-Trakten beruht auf einer verkürzten Va riante des Guanin-reichen Stranges im Nuklease-hypersensitiven Element III 1 des c-MYC-Promotors.D ieser bildet eine stabile, parallele G-Quadruplexstruktur mit drei kurzen Propellerloops. Ein gezieltes Design von spezifischen Formen würde das Repertoire an G-Quadruplexstrukturen erweitern, die z.…”

“…Es würde darüber hinaus aber auch helfen, die beim Faltungsprozess wirkenden Kräfte besser zu verstehen. [5] Das Oligomer ssQ d(GCGTG 3 TCAG 3 TG 3 TG 3 CTCA) mit Überhängen am 5'-u nd 3'-Ende und einer Drei-Nukleotid (3-nt)-sowie zwei Ein-Nukleotid-Sequenzen zwischen den G-Trakten beruht auf einer verkürzten Va riante des Guanin-reichen Stranges im Nuklease-hypersensitiven Element III 1 des c-MYC-Promotors.D ieser bildet eine stabile, parallele G-Quadruplexstruktur mit drei kurzen Propellerloops. [6] Der 3-nt-Loop im ssQ-Quadruplex sollte allerdings auch die Bildung eines Lateralloops ermçglichen, was dann in einer neuen (3+ +1)-Hybridstruktur mit einem Lateralloop, gefolgt von zwei Propellerloops,r esultieren würde (Abbildung 1).…”