Studies of g-quadruplex offer useful indications for designing new therapeutic drugs


Research conducted at the universities of Padua, Milano-Bicocca, and Insubria, in collaboration with the Institute of Photonics and Nanotechnologies of the National Research Council (CNR-IFN), analysed how a secondary structure of DNA evolves in some proto-oncogene promoters.    

Published in the Nucleic Acids Research scientific journal (DOI: 10.1093 / nar / gkab079 - 10.1093 / nar / gkab674), the research conducted included the close observation of behaviours found in G-quadruplexes (G4s), which are secondary structures of DNA, and the possibility of them contributing to the development of a new generation of therapeutic drugs..       

In addition to the double helix, DNA can take the form of non-canonical structures. Interestingly, such structures offer an interesting look into therapeutic approaches to treat many pathologies including tumours, neurodegenerative diseases, infections, and more. Due to their functional importance, non-canonical secondary structures, called G-quartets (G4s), occupy a particularly important place in this context. Pursuing new drugs aimed at these targets has not yet produced the desired results; this is largely because the structure of DNA varies significantly over time and space. 

The researchers analysed the conformational and nanomechanical properties of some G4s present within a particular promoter of a proto-oncogene responsible for the formation of different tumours.  To understand how these structures evolve, the research combined ensemble techniques with single molecule measurements to determine how the matrix of double helix DNA that surrounds them interacts when they form next to each other and how this influences their evolution. Furthermore, the researchers observed that the presence of sequences capable of forming G4s in a stretch of DNA favours the nanomechanical denaturation of the double helix, and hence, initiates gene expression. Since the proteins responsible for DNA transcription occurs during protein synthesis, applying different states of force and torsion on the promoters that induce local denaturation produces the information collected as a high-resolution "photograph" of the chosen target. Finally, it was possible to follow how, and how fast, these sequences fold. This information will help design a next-generation of drugs that can control oncoproteins production in cancer patients.        

“The fundamental contribution of our results is that we have strongly emphasized to the scientific community how it is necessary to understand the evolution over time and space of the targets we aim for to intervene effectively and directly. Our network, which includes scientists with different visions has allowed us to respond to this need by developing innovative and versatile approaches that can now be used more widely"  summarized Professor Claudia Sissi of the Department of Pharmaceutical Sciences of the University of Padua.