SBIR-STTR Award

A new class of biopolymers has been developed that combine the molecular recognition properties of DNA and RNA with expanded functionality and chemical diversity. As in nucleic acids, complementary' strands of the biopolymer recognize each other by Watson-Crick base pairing rules. Further, we have shown that these biopolymers can be replicated in a variety of template-directed biopolymerization reactions using DNA and RNA polymerases. The daughter molecules can themselves encode daughter, molecules. and it should be possible to explore molecular diversity with these molecules via a process of mutation and selection. Unlike DNA and RNA, however. these biopolymers are built from 12 building blocks rather than only 4. Several of these building blocks carry functional groups which provide the biopolymer with much of tile structural versatility of more complex molecules such as proteins. The goal of this project is to establish the feasibility of using DNA and RNA polymerases, previously identified in preliminary, to amplify the biopolymer by a polymerase chain reaction-type process. The commercial products sought are oligonucleotides that are ligands for biological receptors, receptors for biological ligands and amplifiable tags for diagnostic assays that do not cross react with naturally-occurring nucleic acids. PROPOSED COMMERCIAL APPLICATIONS: The commercial applications for novel base pairs and oligonucleotide analogs in which they are contained include drug discovery and diagnostics. Through the creation of molecular diversity, libraries of oligonucleotide analogs with expanded chemical functionality can be created for screening as ligands against target receptors. In the diagnostic area, molecular tags or handles are desired that do not cross-react with naturally-occurring oligonucleotides, but which can form base pairs with a complementary novel base.

Thesaurus Terms:
nucleic acid chemical synthesis, nucleobase, nucleotide analog DNA directed DNA polymerase, DNA directed RNA polymerase, nucleoside triphosphate, oligonucleotide site directed mutagenesisNational Institute of General Medical Sciences (NIGMS)

In vitro selection is a powerful tool for generating new ligands, receptors, and catalysts for targeted receptors, ligands and reactions. In its most commonly used form, in vitro selection begins with libraries of oligonucleotides built from standard bases (A, T, G, and C). The Phase I study demonstrated the feasibility of expanding the functionality of oligonucleotides generated by in vitro selection methods and illustrated how functionalized in vitro selection (FINVIS) yielded products with improved properties in a specific test case. In Phase II, the ability of FINVIS to generate improved ligands, receptors and catalysts will be carefully quantitated and documented. FINVIS will also be used to target two products of medical relevance. Lastly, polymerases that support FINVIS will be further developed by screening and site-directed mutagenesis. The data from Phase II will complete a compelling case for FINVIS against commercial targets, including diagnostic tools, affinity reagents, and therapeutic agents. Commercial partners for Phase III are already being engaged.

Thesaurus Terms:
DNA, catalyst, ligand, oligonucleotide, receptor DNA directed DNA polymerase, chemical binding, enzyme activity, interleukin 1, polynucleotide site directed mutagenesis