Dynamic combinatorial chemistry for nucleic acids

DESCRIPTION (provided by applicant): The proposed research will develop dynamic combinatorial chemistry as a new and innovative strategy to allow a DNA or RNA target in a biological sample to assemble its own template under conditions of dynamic equilibrium. This chemistry incorporates element that allows the template-created primer to primes the synthesis of a strand of DNA complementary to the target. The selectivity of the process is such that a single DNA sequence in a genome as complex as the human genome can be targeted. The architecture of the process, however, allows it to discriminate against single nucleotide changes with the effectiveness of small duplexes. Consistent with the basic research/business mission/plan of the Foundation for Applied Molecular Evolution and Firebird Biomolecular ("We do not make DNA assays. We develop chemistry that makes DNA assays better"), this will create a platform technology that meets specifications that are unavailable at the present time: selectivity of a probe as if it were a long oligonucleotide, but discrimination by the probe as if it were a short oligonucleotide. This platform technology should have application in many assays, including in human diagnostics and research markets. In preliminary studies, a proof of concept showed that this combinatorial chemistry architecture met the novel specifications when the target was DNA. The Phase 1 milestone will be passed if similar success can be obtained with RNA as a target. Potential commercial applications in human medicine are substantial, starting with applications in biomedical research, where these tools will allow us to detect messenger RNA, RNAi, and other RNA molecules important in biology. Several important diagnostics and drug development tools been driven in the past decade through the creation of platform chemical technologies by scientists at the Foundation for Applied Molecular Evolution. Such technologies have commercial impact far beyond their development costs because they deliver a set of chemical performance specifications that is unavailable by existing chemistry. The proposed work will develop another platform technology, this one allowing the detection of nucleic acid targets through a novel combination of dynamic combinatorial chemistry, enzymology, and nucleic acid science.