Energetics of Quadruplex-Drug Recognition in Anticancer Therapy

Abstract

Immortality of tumour cells is strictly correlated to telomerase activity. Telomerase is overexpressed in about 85% of tumour cells and maintains telomere length contributing to cell immortalisation, whereas in somatic cells telomeres progressively shorten until cell death occurs by apoptosis. Different drugs can promote telomeric G-rich overhangs which fold into quadruplex structures that inhibit telomerase activity. Detailed studies on drug-quadruplex complexes are essential to understand quadruplex recognition and address drug design. This review will discuss the energetic aspects of quadruplex-drug interactions with a particular attention to physico-chemical methodologies.

Studying the effect of crowding and dehydration on DNA G-quadruplexes

“…Several biophysical techniques are available for studying quadruplex-ligand and quadruplex-protein interactions, also in the presence of a cosolute, such as isothermal titration calorimetry (ITC), CD, fluorescence, FRET and UV-vis [15,47,53].…”

Applications of Isothermal Titration Calorimetry in Biophysical Studies of G-quadruplexes

“…However, it is important in characterizing and optimizing the drug-target interactions to reveal the thermodynamic nature of the forces that drive the drug-quadruplex binding reaction. A variety of small molecules have been devised to bind and stabilize G-quadruplex structures, ranging from porphyrins to distamycins, acridines, and other polycyclic systems [4]. A number of these molecules capable of stabilizing G-quadruplexes are characterized by a core with a large π-surface that favor stacking interactions with the G-tetrads and, in several cases, they contain side chains that could interact with the grooves of the G-quadruplex structures.…”

“…Moreover, ITC allows dissecting the free energy of binding into enthalpic and entropic components, revealing the overall nature of the forces that drive the binding reaction. Thanks to its versatility and precision, ITC has been proven to be an useful tool to study the energetic aspects of G-quadruplexes’ interactions with other biomolecules, including small ligands [4]. …”

Selective Binding of Distamycin A Derivative to G‐Quadruplex Structure [d(TGGGGT)]4

“…For that reason, the inhibition of telomerase has become an interesting strategy for the anticancer therapy [8]. Since the formation of G-quadruplexes by telomeric DNA inhibits the activity of telomerase, small molecules that stabilize the G-quadruplex structures could potentially be effective chemotherapeutic agents [9]. …”