A new approach using DNA analogues as therapeutic agents is emerging in medicinal chemistry. This is based on regulating expression of genes of disease related proteins/enzymes by blocking their transcription (antigene) or translation (antisense). It is effected through sequence specific binding of complimentary oligonucleotides to either DNA duplex via triplex formation to inhibit reproduction of mRNA or interfere in the translation of the latter to proteins. And following the same principle National Chemical Laboratory (NCL) at Pune has leapfrogged significantly in developing an antisense that would help to combat many diseases.
Talking to this correspondent, Dr. K.N. Ganesh, head, organic chemistry department, NCL said, "The antisense approach is directed against the functioning of mRNA template for the synthesis of proteins. For this approach to be effective, the oligonucleotide analogues must conform to all requirements of a functional drug such as cell permeability, stability in the cells and bioavailability at the desired target." Dwelling on the antisense agent and the lead which NCL has developed he said, "At NCL, we have developed Peptide Nucleic Acids (PNA) as the potential antisense agent and Pyrrolidene as the potential antisense lead." He further stated that during the clinical trials in the lab chemically modified PNA analogues showed better properties than the original PNA. "We decorated the original PNA by attaching some ligands and it showed improved properties. Though biological studies such as cell permeability and the stability of the agent inside the cell is yet to be studied but the biophysical studies of hybridization has shown promising results," said Dr. Ganesh.
If the antisense agent/lead shows the similar promising biological results then some disease which are amenable for treatment by DNA therapeutics includes cancer, viral infections, endocrinological, neurological, autoimmune, bacterial and parasitic diseases.
Commenting on the properties of PNA Dr. Ganesh said, "PNA has several properties that makes it promising for use as a gene targeting agent. PNA is capable of sequence-specific recognition of both DNA and RNA by WC base pairing and the hybrid complexes thus formed exhibit extraordinary high thermal stabilities." He further pointed out that PNA has the capability of invading DNA duplex in a sequence-specific manner, displacing the existing DNA complementary strand and hence is ideal as a therapeutic agent. Highlighting yet another significant property of chemically modified PNA Dr. Ganesh said, "Modified PNAs are very good blood -brain barrier, which makes it possible to have antisense approach towards central nervous system disorders."
Without divulging much details Dr. Ganesh said that some foreign pharma companies have shown interest in the recently developed antisense lead - Pyrrolidene' and will be carrying out biological studies for the same. NCL is also working with National Centre for Cell Science (NCCS) of Pune for biological studies of PNA and yet another Mumbai based Cancer Research Institute, too, is working in collaboration with NCL to study the cell- permeability of PNA. One more significant project that NCL has in hands is to find new targets for development of drug for HIV virus, in collaboration with NCCS.