Exploring the Interaction of G-quadruplex Binders with a (3+1) Hybrid G-quadruplex Forming Sequence within the PARP1 Gene Promoter Region

The enzyme PARP1 is an attractive target for cancer therapy, as it is involved in DNA repair processes. Several PARP1 inhibitors have been approved for clinical treatments. However, the rapid outbreak of resistance is seriously threatening the efficacy of these compounds, and alternative strategies are required to selectively regulate PARP1 activity. A noncanonical G-quadruplex-forming sequence within the PARP1 promoter was recently identified. In this study, we explore the interaction of known G-quadruplex binders with the G-quadruplex structure found in the PARP gene promoter region. The results obtained by NMR, CD, and fluorescence titration, also confirmed by molecular modeling studies, demonstrate a variety of different binding modes with small stabilization of the G-quadruplex sequence located at the PARP1 promoter. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence. This evidence makes the identification of a proper (3+1) stabilizing ligand a challenging goal for further investigation.

Automated summary

PARP1 enzyme is an attractive target for cancer therapy due to its involvement in DNA repair processes. However, the effectiveness of PARP1 inhibitors is being threatened by the emergence of resistance, necessitating the search for alternative strategies to selectively regulate PARP1 activity. A recent study identified a noncanonical G-quadruplex-forming sequence within the PARP1 promoter. This study explores the interaction between known G-quadruplex binders and the G-quadruplex structure found in the PARP gene promoter region, demonstrating various binding modes with small stabilization of the G-quadruplex sequence. Surprisingly, only pyridostatin produces a strong stabilization of the G-quadruplex-forming sequence.