This group is principally interested in the biological effects and targeting for therapeutic purposes of the non-canonical conformations of nucleic acids.
The role of G-quadruplexes and iMotifs in viruses, cancer and neurodegenerative diseases
G-quadruplexes are polymorphic nucleic acid structures identified in gene promoters where they act as transcription regulators. G-quadruplexes have been found in eukaryotic and prokaryotic organisms, and viruses.
The Richter's research group has shown that G-quadruplexes are generally present and conserved in human viruses. The human immunodeficiency virus 1 (HIV-1), which integrates into the human chromosomes and exploits cellular factors to activate transcription, takes advantage of G-quadruplex-mediated transcription regulation. G-quadruplex disruption stimulates promoter activity while G-quadruplex stabilization by small molecules inhibits it, showing a striking parallelism between HIV-1 LTR and eukaryotic promoter G-quadruplexes. We have recently shown that other tetraplex nucleic acid structures, the iMotifs, are also present and regulated in the HIV-1 LTR. In the herpes simplex virus 1 (HSV-1) G-quadruplexes are massively present, their formation is virus cycle-dependent and they peak during viral DNA replication. We are currently further investigating the mechanism of action of G-quadruplexes at the viral level and developing selective compounds.
Research in the Richter's group is also moving towards the understanding of the functions of G-quadruplexes in cancer (sarcomas) and in the X-linked dystonia parkinsonism (XDP) neurodegenerative disease
Targeting non-canonical nucleic acid structures
Small molecules with a wide range of binding affinities have been developed against G-quadruplex nucleic acids.
Unfortunately these do not significantly discriminate between G-quadruplex structures: thus they cannot be straightforwardly employed as antitumor or antiviral drugs.
A key benefit of G-quadruplexes is that they are discrete folded globular DNA structures, and thus small molecules could be specifically designed to selectively recognize and stabilize the target structure for therapeutic purposes.
By biophysical and biochemical analysis, cellular assays, we test small molecules derived from the organic synthesis to assess their activity and mechanism of action.
The main targets are viruses- and tumor-related nucleic acids.