Exploring the interactions between selected ligands and (3+1) PARP G-quadruplex

PARP1 is a nuclear enzyme involved in DNA repair processes. Since its inhibition causes sensitization to DNA damaging chemotherapy (the so-called “synthetic lethality”), several inhibitors have been recently developed and exploited for clinical use. [1] However, the emergence of resistance to PARP1 inhibitors increased the interest towards alternative approaches able to interfere with PARP1 activity. In particular, within the promoter region of PARP1 a characteristic, non-canonical G-quadruplex-forming sequence was identified. [2] A strong correlation between G-quadruplex stabilization in gene promoters and transcriptional regulations has been proposed for several oncogenes. [3] Since no PARP promoter modulators have been described so far, the interaction with a small collection of G4 binders was investigated, taking into account the particular hybrid topology of PARP1 G4. Six structurally diverse compounds, extensively studied and known for showing great affinity towards canonical G4, were selected, and NMR, CD, and fluorescence titration studies were carried out. The results from the physico-chemical analyses, confirmed by molecular modelling, demonstrated that the structural requirements for an optimal interaction between the ligand and this peculiar G4 portion are quite strict. Overall, the studied compounds can be considered as a starting point for the identification of the key features necessary for a selective interaction with the PARP promoter G4.