Grant: Operating Grant

Messenger RNA (mRNA) encodes for proteins that give rise to disease states like cancer and HIV-Aids. Proteins are usually the targets of drugs but mRNA is also a target because the ability to destroy a molecule of mRNA results in not producing 100s of molecules of protein. There is a great need to target RNA, which is involved in viral diseases like HIV and hepatitis where RNA codes for viral proteins, as well as in cancer where RNA codes for cancer-causing proteins. DNAzymes are molecules of DNA that can catalytically destroy molecules of RNA. This means that one molecule of DNAzyme can destroy many molecules of RNA such that less DNAzyme needs to be administered because its catalytic activity enhances potency. Our ability to cleave RNA comes from our ability to recognize RNA, which comes from our knowledge of the genetic code defined by the famous scientists Watson and Crick. They established base-pairing rules where G recognizes C, and A recognizes T, and vice-versa. Using oligonucleotides of DNA, we can recognize a single sequence of RNA with high specificity thus allowing us to target that RNA without interfering with other RNA sequences that produce good proteins. This targeting approach will be merged with our ability to discover and synthesize totally new DNAzymes that will recognize a disease-associated RNA target and then catalyze the destruction of the RNA. Our approach is novel and different from other uses of DNAzymes in that we add synthetic, drug-like functionalities to the DNAzymes that allow them to operate without Mg2+, a positively charged metal ion cofactor that is not very abundant in cells. Its absence in cells means that most DNAzymes developed so far are not very active. Our work deals with using synthetic medicinal chemistry to make DNAzymes active in cells while using Watson-Crick rules to bring about highly specific targeting of RNAs that give rise to diseases such as cancer, HIV and hepatitis