DEVELOPMENT OF MODULAR NUCLEIC ACID SURROGATES

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The overall aim of this project is to develop a new class of nucleic acid surrogates capable of sequence specific binding to single stranded DNA & RNA as well as double-stranded DNA targets. The repeating structural units for the proposed modules include peptide- and peptidomimetic-based nucleic acid surrogates. Once synthesized (in suitably protected form), the nucleobase-containing modules will be linked together via peptide and/or amide bonds to give the required oligomeric structures having defined nucleobase sequences. For each structural type, the research plan will entail: (1) computational evaluation of each surrogate to see if it can accommodate hybridization to complementary nucleic acid targets, (2) molecular synthesis and characterization of oligomeric structures having defined sequences of nucleobases, and finally (3) physicochemical evaluation of the hybridization potential of the resulting surrogates with specific nucleic acid target sequences. Iteration of this rational approach (design, synthesis, & evaluation) is expected to lead to nucleic acid surrogates that bind specifically to their nucleic acid target sequences. Alternatively, a combinatorial synthesis/affinity chromatography approach will be used to produce mixed residue surrogates capable of sequence specific triplex formation and molecular recognition of unusual nucleic acid tertiary structures (loops, junctions, etc.). If successful, this research project could lead to more effective antisense/antigene probes and/or drug carriers for use as genetically-based medicines in the treatment of viral infections and cancer.