UCLA researchers in the Department of Chemistry and Biochemistry have developed a novel method of metal-mediated base pair stabilization in vivo, with additional applications in the detection of small nucleic acids and regulation of transition metal catalysis.
BACKGROUND:
Recent studies of the interactions between transition metals and DNA have led to the development of metalloDNA based therapeutics and nanotechnology. In particular, metal-mediated base pairs (MMBP), transition metal-coordination complexes incorporated into DNA base pairs, are ideally suited to expand nucleic acid functionality beyond their natural context for use in biotechnology. Possible applications of the site-specific incorporation of transition metals include charge transfer through DNA, regulation of organometallic reactivity, recognition of specific nucleic acid sequences, as well as the development of metal sensors and metal-responsive materials. At present, Ag(I) and Hg(II) are the only two metals that have demonstrated ability to specifically coordinate to canonical DNA mismatches rather than base mimics. However, both Ag(I) and Hg(II) are unfit for applications in vivo due to their inherent toxicity. The investigation of new metals that may be incorporated into canonical bases is crucial for further improvements in metal-based therapeutics and advances in DNA based nanotechnology.
INNOVATION:
UCLA researchers have demonstrated that Au(I) is able to coordinate specifically to canonical DNA mismatches, resulting in a highly stabilizing Au(I) metal-mediated base pair. This Au(I) metal-metal base pair is amenable to applications in vivo, unlike previously investigated metalloDNA involving Ag(I) and Hg(II). The coordination of Au(I) within a DNA mismatch yields the highest reported thermal stability for a MMBP composed of naturally occurring DNA bases. Further, this DNA-Au(I) catalytic complex allows for regulation of the transition metal catalytic activity through interactions with small DNA/RNA. This represents one of the first examples of an organometallic catalyst that may be regulated by biological stimuli. The catalysis may be performed on paper and is a simple, inexpensive method for detection of small nucleic acids, such as mRNA and other small molecules in biological samples.
POTENTIAL APPLICATIONS:
• In vivo metal-based therapeutics for DNA mismatch stabilization
• Detection of small nucleic acids, such as mRNA
• Modulation of transition metal catalyst reactivity through interactions with native biological molecules such as RNA and RNA
ADVANTAGES:
• Increased stability of Au(I) in cytosine-cytosine mismatches and cytosine-adenine mismatches compared to Ag(I) and Hg(II)
• Au(I) may be used for applications in vivo
• Simple, inexpensive testing of biological sample for mRNA and small molecules
• Catalysis may be performed on paper
DEVELOPMENT-TO-DATE:
This invention has been evaluated for its thermal stability, base-pairing energy, and potential structural changes to DNA via circular dichroism, which confirm increased in vivo stability of DNA mismatches. Further, the invention has shown successful modulation of reactivity by small RNA sequences.