PNA Peptide Nucleic Acid
PNAPeptide nucleic acids (PNA) are DNA mimics with a pseudopeptide backbone. PNA is an extremely good structural mimic of DNA (or RNA), and PNA oligomers are able to form very stable duplex structures with Watson-Crick complementary DNA, RNA (or PNA) oligomers, and they can also bind to targets in duplex DNA by helix invasion. Therefore, these molecules are of interest in many areas of chemistry, biology, and medicine including drug discovery, genetic diagnostics, molecular recognition and the origin of life. The history, properties and applications of PNA in drug discovery and DNA detection is presented in the book Peptide Nucleic Acids
The double helix of DNA is Nature's simple and elegant solution to the problem of storing, retrieving, and communicating the genetic information of a living organism. DNA has many important characteristics that allow it to perform these functions. Two of the most important properties are the specificity and the reversible nature of the hydrogen bonding between complementary base pairs, properties which allow the strands of the double helix to be unwound and then rewound in exactly the same configuration.
The field of life science realized early on the important implications of these traits. If specific, single strands of DNA could be synthesized, then the base sequences of genes could be studied and manipulated using these defined molecules. With the advent of efficient chemistries for DNA/RNA synthesis including automated instrumentation, these opportunities became reality. Synthetic oligonucleotides are now indispensable tools for life scientists, with many applications in molecular biology, genetic diagnostics, and most likely also soon in medicine.
PNA was originally designed as a ligand for the recognition of double stranded DNA. The concept was to mimic an oligonucleotide binding to double stranded DNA via Hoogsteen base pairing in the major groove. Thus the nucleobases of DNA were retained, but the deoxyribose phosphodiester backbone of DNA was replaced by a pseudo-peptide backbone that according to computer model building was homomorphous with the DNA backbone. In theory a neutral (peptide) backbone should improve the triplex binding capability of the ligand, and we believed that the pseudo peptide backbone was a good chemical scaffold that would allow us to design recognition moieties that went beyond homopurine targets.
It was, however, apparent that the PNA designed for triplex formation would also be a mimic of single stranded nucleic acids by default. Although, it was impossible to imagine all the properties and applications that could be developed based on the neutral backbone, it was intriguingto attempt to make a water soluble mimic of an oligonucleotide with a neutral backbone. The potential of the resulting structure as an antisense agent and as a molecular biology tool was obvious although abstract at the point of conception. The pursuit of a neutral backbone drove the design, and the leap to peptide (or amide) chemistry was easy because of the well-established robustness and flexibility of solid phase peptide synthesis (SPPS) technology. During the early stages of the design many structures were considered. However, by applying additional criteria for the structure such as, rigidity, water solubility and not at least chemical accessibility, the structure now known as PNA came into being. The very first experiments conducted with homo-thymine PNAs clearly demonstrated that these bound sequence-specifically to double stranded DNA. It was realized that two homothymine PNAs had formed a triplex with the homoadenine target in the double stranded DNA, while displacing the homothymine strand in the DNA target. Later it was found that PNAs with both purine and pyrimidine bases form very stable duplexes with DNA and RNA, although not with the extremely high stability of the homo-pyrimidine 2PNA/DNA triplexes, but still more stable than the corresponding DNA/DNA and DNA/RNA duplexes. With many properties that set them apart from traditional DNA analogs, PNAs have added a new dimension to synthetic DNA analogs and mimics in molecular biology, diagnostics, and therapeutic.
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