Targeting unique nucleic acid structures with small molecules.

摘要

Nucleic acids are the central biomolecules of life, encoding all the genetic information necessary for cellular metabolism and replication. Binding of small molecules to DNA or RNA can perturb their function as well as interactions with proteins or other nucleic acids. Disrupting these key intermolecular interactions with low molecular weight ligands is a promising strategy for the development of new therapeutics. Our efforts have been focused on three different areas. First, the formation of triple helices has been shown to affect the normal binding of duplex nucleic acids with enzymes such as DNA polymerase. Stabilizing these triple helices with ligands that exploit pi-pi stacking interactions can potentially assist in selective modulation of gene expression. We have demonstrated that an extended phenanthridinium core selectively binds to DNA triple helices. Second, a diminishing number of last resort antibiotics are effective against the continuing emergence of drug resistant bacteria. Mimicking the characteristics of current antibiotics with new molecular scaffolds is one strategy to overcome antimicrobial resistance mechanisms. With this in mind, we have initiated the synthesis of a small library of heterocycle-deoxystreptamine conjugates to potentially mimic the efficacy of aminoglycosides, a class of RNA-binding antibiotics. Finally, the rapid screening of low molecular weight ligands is critical to identifying new, potential nucleic acid binders. We have developed a novel, real-time fluorescence-based assay for monitoring ligand binding to the HIV-1 DIS, which has led to the discovery of new natural and semi-synthetic binders to this interesting viral RNA target. Taken together, our research highlights the potential benefits of targeting nucleic acids: the selective modulation of gene expression, overcoming current antibiotic resistance mechanisms, and inhibiting replication of retroviruses.