Emerging roles of i-motif in gene expression and disease treatment

Abstract

As non-canonical nucleic acid secondary structures consisting of cytosine-rich nucleic acids, i-motifs can form under certain conditions. Several i-motif sequences have been identified in the human genome and play important roles in biological regulatory functions. Due to their physicochemical properties, these i-motif structures have attracted attention and are new targets for drug development. Herein, we reviewed the characteristics and mechanisms of i-motifs located in gene promoters (including c-myc, Bcl-2, VEGF, and telomeres), summarized various small molecule ligands that interact with them, and the possible binding modes between ligands and i-motifs, and described their effects on gene expression. Furthermore, we discussed diseases closely associated with i-motifs. Among these, cancer is closely associated with i-motifs since i-motifs can form in some regions of most oncogenes. Finally, we introduced recent advances in the applications of i-motifs in multiple areas.

Keywords: biological activities; gene-targeted therapy; i-motif; ligand compounds; molecular mechanism; oncogene; telomere.

FIGURE 1

Structures of the i-motif and G4.

FIGURE 2

Structures of compounds (1–9).

FIGURE 3

Structures of compounds (10–21).

FIGURE 4

Structures of compounds (22–28). *Lattice water and chloride ions are omitted.

FIGURE 5

Structure of [Ru(bpp) ₂ ] ²⁺ (29). Crystal structures of cis (30), mer (31), and trans (32).

FIGURE 6

Structures of compounds (33–55).

FIGURE 7

Usual modes of ligands binding to the i-motif. (A) Binding to the major external groove of the i-motif owing to large steric hindrance and ionic strength. (B) Embedding in C-C⁺ base pairs by π-π stacking. (C) Stacking at two ends of the i-motif in the presence of Van der Waals and electrostatic forces. (D) Binding to hairpin species in the central loop region of the i-motif due to steric hindrance and molecular length.

FIGURE 8

Mechanism of i-motifs in vivo. The i-motif DNA sequence folds into i-motif structures in specific conditions, including acid pH, K⁺, or some small molecules. I-motifs mainly have two effects: firstly, they directly bind to proteins such as hnRNP A1, hnRNP K, and hnRNP LL; second, they can directly interact with ligands. The result is switching gene expression on or off. Activated genes produce corresponding proteins after transcription. These proteins interact with other factors and form complexes that are transported to certain tissue. The release of these proteins can lead to tumors, neuropathy, aging, HIV, and autoimmune disease.

FIGURE 9

Structures of compounds (56–61).