4. SYNTHESIS AND EVALUATION OF MODIFIED NUCLEIC ACIDS

Chemically modified oligodeoxynucleotides (ODNs) have received much attention in the search for potential therapeutic and diagnostic agents, such as developing antiviral and anticancer agents, and in the study of numerous biochemical and biological processes such as controlling gene expression. Most of the reported chemically modified ODNs have been hampered by one or more of the following difficulties: low nuclease stability, weak specificity, limited cell penetration, lack of RNase H effect, nonspecific binding to certain proteins, and poor aqueous solubility. Furthermore, the current synthetic methods for the synthesis of modified ODNs cannot be generalized for the synthesis of novel modified ODNs and oligomers mimicking natural oligonucleotides. Studies of the effects of backbone modifications on the conformational, physical and biological properties of nucleic acids are crucial importance in realizing the therapeutic goals. These studies can be feasible by new and improved methods for the solid phase synthesis of backbone modified oligos.

                           ODNs containing unmodified and modified internucleotide bridges 

Synthesis and evaluation of biochemical utility of ODNs containing diphosphodiester internucleotide linkages were carried out in our laboratory. These studies established a new family of chemically modified ODNs. These data indicate that modified ODNs are able to form duplexes with their complementary modified or unmodified chains based on thermal denaturation studies and CD analysis. The modified oligomers were resistant to degradation by DNase I and 3'-exonuclease I under conditions where unmodified ODNs were degraded and showed multiple bands. The results of this investigation was recently published:

1. Ahmadibeni, Y., Parang, K., Synthesis and evaluation of oligodeoxynucleotides containing diphosphodiester internucleotide linkages. Angew. Chem. Int. Ed. (2007) 46, 4739-4743.

The long-term objective of this proposal to synthesize of novel modified ODNs and oligomers with optimized bio-physical properties. The central hypothesis of this proposal is that modified ODNs or oligomers with enhanced stability to nuclease, cell penetration ability, selectivity, binding affinity toward complementary nucleic acids, and the melting temperature (Tm) of formed duplex can be obtained by modification of phosphodiester internucleotide linkage and/or replacing the carbohydrate moiety. The focus will be on synthesizing and evaluating different classes of ODNs and oligomers containing novel linkages.