The evolving world of protein-G-quadruplex recognition: a medicinal chemist's perspective

Abstract

The physiological and pharmacological role of nucleic acids structures folded into the non canonical G-quadruplex conformation have recently emerged. Their activities are targeted at vital cellular processes including telomere maintenance, regulation of transcription and processing of the pre-messenger or telomeric RNA. In addition, severe conditions like cancer, fragile X syndrome, Bloom syndrome, Werner syndrome and Fanconi anemia J are related to genomic defects that involve G-quadruplex forming sequences. In this connection G-quadruplex recognition and processing by nucleic acid directed proteins and enzymes represents a key event to activate or deactivate physiological or pathological pathways. In this review we examine protein-G-quadruplex recognition in physiologically significant conditions and discuss how to possibly exploit the interactions' selectivity for targeted therapeutic intervention.

Fig. 1

Three-dimensional structure of the GGTTGGTGTGGTTGG aptamer bound to α-thrombin. PDF 1HUT. The G4 component is highlighted in red, the protein in yellow. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Three-dimensional structure of the sequence GGGGTTTTGGGG bound to Oxytricha nova TEBP heterodimer in a quaternary complex containing both single-stranded DNA and G4 folded DNA. PDB 1JB7. The G4 component is highlighted in red and the corresponding protein contacting surface in yellow, the single-stranded DNA fragment is in blue and the corresponding protein contacting surface in green. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)