Design of DNA and RNA G-quadruplex stabilizers

Abstract

The guanine-quadruplex (G4) is a particular secondary structure of DNA and RNA involved in several key functions of the cell cycle. G4 sequences are present in the human genome at both the DNA and RNA levels. This makes G4s potential targets for new anticancer drugs. G4 structures have also recently been identified in the genome of DNA and RNA viruses and there is a direct relationship between the presence of G4 and the regulation of key steps for virus replication in the host organism. For this reason, the design of molecules that are able to stabilize the quadruplex conformations of DNA and RNA is of increasing importance today, as demonstrated by the growing number of works published in the literature. As part of the Drug Discovery projects, in 2024 the group will finalize the creation of the first tool for predicting the activity of G-quadruplex DNA and RNA stabilizers. This tool based on ligand-based approaches will be published online and made available to the scientific community for the design and prediction of new ligands. By the end of 2025, the online tool will be enriched with structural data of quadruplex structures available in public databases and will be able to propose not only the prediction of generic activity on quadruplex structures, but also the specific sequences on which a given ligand will be able to show greater affinity.

Impact

 The discovery of small molecules with stabilizing power towards non-canonical structures of DNA and RNA has great potential for applications mainly in the oncology field and in other therapeutic areas such as infectious diseases (recent discoveries have demonstrated the presence of these structures also in viral genomes). The Molecular Informatics group at Ri.MED Foundation is engaged, in collaboration with the University of Palermo and the University of Paris Cité, in the design of molecules able to stabilize the DNA and RNA quadruplex structures, while maintaining the druglikeness characteristics. This last aspect represents the greatest challenge in pharmaceutical design and would lead to a very important step forward in the design of quadruplex stabilizers for therapeutic purposes.

Pipeline