Peptide nucleic acid (PNA) is an artificially synthesized
polymer
A polymer (; Greek '' poly-'', "many" + ''-mer'', "part")
is a substance or material consisting of very large molecules called macromolecules, composed of many repeating subunits. Due to their broad spectrum of properties, both synthetic a ...
similar to
DNA or
RNA.
Synthetic peptide nucleic acid
oligomers have been used in recent years in molecular biology procedures, diagnostic assays, and
antisense therapies. Due to their higher binding strength, it is not necessary to design long PNA oligomers for use in these roles, which usually require oligonucleotide probes of 20–25 bases. The main concern of the length of the PNA-oligomers is to guarantee the specificity. PNA oligomers also show greater specificity in binding to complementary DNAs, with a PNA/DNA base mismatch being more destabilizing than a similar mismatch in a DNA/DNA duplex. This binding strength and specificity also applies to PNA/RNA duplexes. PNAs are not easily recognized by either
nucleases or
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s, making them resistant to
degradation
Degradation may refer to:
Science
* Degradation (geology), lowering of a fluvial surface by erosion
* Degradation (telecommunications), of an electronic signal
* Biodegradation of organic substances by living organisms
* Environmental degradatio ...
by
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
s. PNAs are also stable over a wide
pH range. Though an unmodified PNA cannot readily cross the cell membrane to enter the cytosol, covalent coupling of a
cell penetrating peptide to a PNA can improve cytosolic delivery.
PNA is not known to occur naturally but
N-(2-aminoethyl)-glycine (AEG), the backbone of PNA, has been hypothesized to be an early form of genetic molecule for life on earth and is produced by
cyanobacteria and is a neurotoxin.
PNA was invented by
Peter E. Nielsen (Univ. Copenhagen), Michael Egholm (Univ. Copenhagen), Rolf H. Berg (Risø National Lab), and Ole Buchardt (Univ. Copenhagen) in 1991.
Structure
DNA and RNA have a
deoxyribose
Deoxyribose, or more precisely 2-deoxyribose, is a monosaccharide with idealized formula H−(C=O)−(CH2)−(CHOH)3−H. Its name indicates that it is a deoxy sugar, meaning that it is derived from the sugar ribose by loss of a hydroxy group. D ...
and
ribose sugar backbone, respectively, whereas PNA's backbone is composed of repeating
N-(2-aminoethyl)-glycine units linked by
peptide bonds. The various
purine and
pyrimidine bases are linked to the backbone by a
methylene bridge
In organic chemistry, a methylene bridge, methylene spacer, or methanediyl group is any part of a molecule with formula ; namely, a carbon atom bound to two hydrogen atoms and connected by single bonds to two other distinct atoms in the rest of t ...
(--) and a
carbonyl
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups. A compound containi ...
group (-(C=O)-). PNAs are depicted like
peptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s, with the
N-terminus at the first (left) position and the
C-terminus at the last (right) position.
Binding
Since the backbone of PNA contains no charged
phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosph ...
groups, the binding between PNA/DNA strands is stronger than between DNA/DNA strands due to the lack of electrostatic repulsion. Unfortunately, this also causes it to be rather hydrophobic, which makes it difficult to deliver to body cells in solution without being flushed out of the body first. Early experiments with homopyrimidine strands (strands consisting of only one repeated
pyrimidine base) have shown that the T
m ("melting" temperature) of a 6-base thymine PNA/adenine DNA double helix was 31 °C in comparison to an equivalent 6-base DNA/DNA duplex that
denatures at a temperature less than 10 °C. Mixed base PNA molecules are true mimics of DNA molecules in terms of base-pair recognition. PNA/PNA binding is stronger than PNA/DNA binding.
PNA translation from other nucleic acids
Several labs have reported sequence-specific polymerization of peptide nucleic acids from DNA or RNA templates.
Liu and coworkers used these polymerization methods to evolve functional PNAs with the ability to fold into three-dimensional structures, similar to proteins,
aptamer
Aptamers are short sequences of artificial DNA, RNA, XNA, or peptide that bind a specific target molecule, or family of target molecules. They exhibit a range of affinities ( KD in the pM to μM range), with little or no off-target bindin ...
s and
ribozyme
Ribozymes (ribonucleic acid enzymes) are RNA molecules that have the ability to catalyze specific biochemical reactions, including RNA splicing in gene expression, similar to the action of protein enzymes. The 1982 discovery of ribozymes demons ...
s.
Delivery
In 2015, Jain ''et al.'' described a trans-acting DNA-based amphiphatic delivery system for convenient delivery of
poly A tailed uncharged nucleic acids (UNA) such as PNAs and
morpholino
A Morpholino, also known as a Morpholino oligomer and as a phosphorodiamidate Morpholino oligomer (PMO), is a type of oligomer molecule (colloquially, an oligo) used in molecular biology to modify gene expression. Its molecular structure contain ...
s, so that several UNA's can be easily screened ''ex vivo''.
PNA world hypothesis
It has been hypothesized that the earliest life on
Earth
Earth is the third planet from the Sun and the only astronomical object known to harbor life. While large volumes of water can be found throughout the Solar System, only Earth sustains liquid surface water. About 71% of Earth's surfa ...
may have used PNA as a genetic material due to its extreme robustness, simpler formation, and possible spontaneous
polymerization
In polymer chemistry, polymerization (American English), or polymerisation (British English), is a process of reacting monomer molecules together in a chemical reaction to form polymer chains or three-dimensional networks. There are many fo ...
at 100 °C (while water at standard pressure boils at this temperature, water at high pressure—as in deep ocean—boils at higher temperatures). If this is so, life
evolved
Evolution is change in the heritable characteristics of biological populations over successive generations. These characteristics are the expressions of genes, which are passed on from parent to offspring during reproduction. Variation ...
to a DNA/RNA-based system only at a later stage. Evidence for this PNA world hypothesis is, however, far from conclusive. If it existed though, it must have preceded the widely accepted
RNA world
The RNA world is a hypothetical stage in the evolutionary history of life on Earth, in which self-replicating RNA molecules proliferated before the evolution of DNA and proteins. The term also refers to the hypothesis that posits the existen ...
.
Applications
Applications include alteration of gene expression - both as inhibitor and promoter in different cases, antigene and antisense therapeutic agent, anticancer agent, antiviral, antibacterial and antiparasitic agent, molecular tools and probes of
biosensor
A biosensor is an analytical device, used for the detection of a chemical substance, that combines a biological component with a physicochemical detector.
The ''sensitive biological element'', e.g. tissue, microorganisms, organelles, cell rece ...
, detection of DNA sequences, and nanotechnology.
PNAs can be used to improve high-throughput 16S ribosomal RNA gene sequencing of plant and soil samples by blocking amplification of contaminant plastid and mitochondrial sequences.
Cellular – Functional Antagonism/Inhibition.
In 2001, Strauss and colleagues reported the design of an application for PNA oligomers in living mammalian cells. The Xist chromatin binding region was first elucidated in female mouse fibroblastic cells, and embryonic stem cells though the use of a PNA molecular antagonist. The novel PNA approach directly demonstrated function of a lncRNA. The long non-coding (lncRNA) RNA, Xist directly binds to the inactive X-chromosome. Functional PNA inhibition experiments revealed that specific repeat regions of the Xist RNA were responsible for chromatin binding, and hence could be considered domain regions of the RNA transcript. The PNA molecular antagonist was administered to living cells and functionally inhibited the association of Xist with inactive X-chromosome using the approach for studying noncoding RNA function in living cells called peptide nucleic acid (PNA) interference mapping. In the reported experiments, a single 19-bp antisense cell-permeating PNA targeted against a particular region of Xist RNA caused the disruption of the Xi. The association of the Xi with macro-histone H2A is also disturbed by PNA interference mapping.
["Beletskii et al 2001"/]
See also
*
Clicked peptide polymer
*
Glycol nucleic acid
*
Oligonucleotide synthesis
*
Peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, compounds where multiple amino acids are linked via amide bonds, also known as peptide bonds. Peptides are chemically synthesized by the condensation reaction of the carboxyl ...
*
Threose nucleic acid Threose nucleic acid (TNA) is an artificial genetic polymer in which the natural five-carbon ribose sugar found in RNA has been replaced by an unnatural four-carbon threose sugar.Schöning, K. U. ''et al.'' Chemical etiology of nucleic acid structu ...
References
Further reading
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{{DEFAULTSORT:Peptide Nucleic Acid
Nucleic acids
Origin of life