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Peptide Nucleic Acids (PNA)

Peptide Nucleic acids are synthetic oligonucleotides that resist protease degradation and are used to induce repair at site specific triplex formation regions on DNA genomic sites. PNAs are able to bind with high affinity and sequence specificity to a complementary  DNA sequence through Watson-Crick base pairing binding and are able to form triple helices through parallel orientation Hoogsteen bonds with the PNA facing the 5’-end of the DNA stand. The PND-DNA triplex are stable due to PNAs are comprised of a neutrally charged pseudopeptide backbone which is able to bind to the double stranded DNA (dsDNA) sequence . Similar to homopyrimidine in TFOs, Homopyrimidine in PNAs are able to form a bond with the complementary Homopurine in target sequence of the dsDNA. These DNA analogues are able to bind to dsDNA through exploiting ambient DNA conditions and different predicting modes of recognition which different from TFOs, which bind though the major groove recognition of the dsDNA.

One of the predicting modes of recognition used for recognition is through a duplex invasion. Within mixed A–T/G–C dsDNA sequence targets a pair of pseudo-complementary (pc) PNAs are able to bind to dsDNAs via double invasion though the simultaneous formation of diaminopurine (D) and thiouracil (U^s) which substitute for adenine and thymine, respectively. The pcPNA pair form a D-T and U^s -A and G-C or C-G Watson-Crick paired PNA-DNA helix with each of complementary DNA strands. Another form of recognized duplex invasion at targeted sequence can occur in dsDNA containing mixed T–C sequences. This form of duplex invasion is achieved through a complimentary sequence of homopurine PNA oligomers.  This triplex is formed from a PNA-DNA hybrid that binds anti-parallel with the complementary DNA sequence and results in a displaced non-complimentary DNA strand. The strand invasion.

         

           Additionally, PNA can be modified to form “clamp” triplex structures at the target site . One type of “clamp” formed, is a flexible linker that binds two PNA molecules to form a bis-PNA structure. The bis-PNA structure forms a PNA-DNA-PNA triplex at the target site.  A tail clamp PNA (tcPNA) is also another form of triplex clamp that can also be formed. TcPNAs contain an extended 5-10 bp tail that forms a PNA/DNA duplex in addition to a PNA-DNA-PNA “clamp”. This allows for more specified PNA binding without the need of a homopyrimidie/pyridine stretch.

Historically, TFO binding has been shown to inhibit transcription, replication and protein binding to DNA. A TFO tethered to mutagens has also been shown to promote DNA damage and induce mutagenesis. Although TFO have been known to hinder transcription and replication of DNA, recent studies have shown that TFO can be utilized to mediate site specific gene modifications both in vitro and in vivo. Another recent study has also shown that TFOs can be used for suppression of oncogenes and proto-oncogenes to reduce cancer cell growth.