Developing Novel G-Quadruplex Ligands: from Interaction with Nucleic Acids to Interfering with Nucleic Acid–Protein Interaction

Abstract

G-quadruplex is a special secondary structure of nucleic acids in guanine-rich sequences of genome. G-quadruplexes have been proved to be involved in the regulation of replication, DNA damage repair, and transcription and translation of oncogenes or other cancer-related genes. Therefore, targeting G-quadruplexes has become a novel promising anti-tumor strategy. Different kinds of small molecules targeting the G-quadruplexes have been designed, synthesized, and identified as potential anti-tumor agents, including molecules directly bind to the G-quadruplex and molecules interfering with the binding between the G-quadruplex structures and related binding proteins. This review will explore the feasibility of G-quadruplex ligands acting as anti-tumor drugs, from basis to application. Meanwhile, since helicase is the most well-defined G-quadruplex-related protein, the most extensive research on the relationship between helicase and G-quadruplexes, and its meaning in drug design, is emphasized.

Dynamics Studies of DNA with Non-canonical Structure Using NMR Spectroscopy

“…G4 targeted ligands have recently emerged as a promising strategy for developing anticancer drugs. Because telomerase is highly expressed in many kinds of tumor cells, telomeric G4s have been considered as a potential target for ligands that bind to and stabilize the G4 for inhibition of telomerase [56,57]. G4s in oncogene promoters such as c-MYC, c-kit, and KRAS are also important in cancer biology.…”

“…It is known that c-MYC transcription is upregulated in 80% of solid tumors, and it could be regulated by c-MYC targeted therapeutics [58,59]. There are several recent reviews of the design, synthesis, and therapeutic potential of G4 ligands [18,57,60].…”

Selective recognition of human telomeric G-quadruplex with designed peptide via hydrogen bonding followed by base stacking interactions

“…[7][8][9] In past few years; efforts are directed towards the development of G4 binding ligands with increasing specicity and selectivity for different strand orientation and loop length. [10][11][12] Much research has focussed on reporting ligands having a planar aromatic surface which is accessible for G4 binding by p-stacking interactions. 11 To further increase the selectivity and the affinity of a ligand, efforts are towards the incorporation of neutral or cationic side chain which binds in the grooves or loops of the G4 structure by means of electrostatic as well as hydrogen-bonding interactions.…”

“…[10][11][12] Much research has focussed on reporting ligands having a planar aromatic surface which is accessible for G4 binding by p-stacking interactions. 11 To further increase the selectivity and the affinity of a ligand, efforts are towards the incorporation of neutral or cationic side chain which binds in the grooves or loops of the G4 structure by means of electrostatic as well as hydrogen-bonding interactions. 10 However, higher selectivity of the ligand to bind with G4 in the presence of excess amounts of double-stranded DNA is still a major challenge.…”

“…Moreover, tryptophan (W) residues were incorporated to provide an aromatic rings for p-p stacking interactions that can t within the G-quartet planes, as demonstrated in recent studies. [11][12][13][14][15][16] In contrast to previous small molecules and peptide targeting DNA, 17 we did not introduce positive residues such as arginine and lysine, to reduce a non-specic binding with other DNA structures, including DNA duplex. Based on the molecular design, it is possible to consider that binding modes of QW10 are hydrogen bonding and stacking interaction.…”