Quadruplex-Forming Oligonucleotides as Tools in Anticancer Therapy and Aptamers Design: Energetic Aspects

Abstract

Recent investigations on the G-quadruplex motif propose a new strategy for the making of antitumour drugs. Quadruplex-drug complexes have been suggested to inhibit telomerase activity; further, aptamers based on the quadruplex motif have been proved useful as tools aimed at binding and inhibiting particular proteins, thus serving as pharmaceutically active agents. However, the design of new aptamers is difficult because many factors affecting their activity and stability have not still been clarified. The knowledge of the energetics of quadruplex formation is a crucial point in view of their potential therapeutic utilization both as targets as well as therapeutic agents. In this review the energetic aspects of both quadruplex assembly and quadruplex-ligand interactions are discussed together with a summary of recent studies on physico-chemical properties in solution of quadruplex structures obtained from synthetic aptamers, including PNA-DNA chimeras.

Identification of tunnels in proteins, nucleic acids, inorganic materials and molecular ensembles

“…Among them, the quadruplex structures formed by guanine-rich nucleic acid sequences have received significant attention recently because of growing evidence for their role in important biological processes and as therapeutic targets [26][27][28][29][30][31]. G-quadruplex DNA has been suggested to regulate DNA replication and may control cellular proliferation.…”

Energetic aspects of locked nucleic acids quadruplex association and dissociation

“…[2][3][4][5][6][7] In addition to the in vivo biological role, quadruplexes may play within cellular structures, their biomedical relevance has recently expanded due to the identification of their potential use as pharmaceutically active agents. 8 Indeed, some examples exist where aptameric nucleic acids possess quadruplex structures. 9 Among these, the most studied aptamer is the Thrombin-Binding-Aptamer, whose oligonucleotide sequence d(GGTTGGTGTGGTTGG) adopts an intramolecular G-quadruplex structure in solution.…”

Physico-chemical analysis of G-quadruplex containing bunch-oligonucleotides

“…The level of interest in these structures has increased due to growing evidences supporting the hypothesis of a relevant role of G-quadruplex structures in key biological processes [10][11][12][13]. Formation of Gquadruplex structures at telomeric ends of chromosomal DNA and their stabilization by specific ligands has been shown to inhibit telomerase thus affecting the lifespan of the cells of a number of cancer types characterized by a high level of telomerase expression [14][15][16]. Furthermore, G-quadruplex structures have been found in the promoter region of the c-myc oncogene [17] and G-rich sequences are a recurring theme in the promoter regions of many oncogenes, for example c-yes [18], c-src [19], c-sis [20], c-rel [21].…”

“…These unfavourable kinetic parameters could be disadvantageous in view of their potential therapeutic use. The synthesis of modified quadruplex structures could overcame these drawbacks and produce new aptamers with better physicochemical and biological properties, which could have significant impact on biotechnology and drug developments [14,35,36]. In this frame, the synthesis of a bunch-[d(TG 4 T)] 4 (Fig.…”