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Peptide nucleic acid based recognition
Peptide nucleic acids (PNA) are synthetic DNA analogues
or mimics with a polyamide backbone instead of a sugar
phosphate bone (Egholm et al., 199 ). Of significant
importance to biosensing, PNAs exhibit superior
hybridization characteristics and improved chemical and
enzymatic stability compared to nucleic acids (Brandt
and Hoheisel, 2004). Both double and triple stranded
complexes are capable of being formed by PNA in
association with nucleotides (Nakamura and Karube,
200 ). As shown in Fig. 9, the negatively charged ribose-
phosphate backbone of nucleic acids is replaced by an
uncharged N-(2-aminoethyl)-glycine scaffold to which the
nucleobases are attached via a methylene carbonyl linker.
Because the intramolecular distances and configuration
of the nucleobases are similar to those of natural DNA
molecules, specific hybridization occurs between PNAs
and cDNA or RNA sequences. The uncharged nature
of PNAs is responsible for a better thermal stability
of PNA–DNA duplexes compared with DNA–DNA
equivalents and, as a result, single-base mismatches
have a considerably more destabilizing effect (Egholm
et al., 199 ). As with DNA, the decrease in duplex
stability depends on the position of the mismatch within
the sequence (Igloi, 1998). The neutral amide backbone
also enables PNA to hybridize to DNA molecules in low-
salt conditions because no positive ions are necessary
for counteracting the interstrand repulsion that hampers
duplex formation between two negatively charged nucleic
acids. Consequently, the abundance and stability of
intramolecular folding structures in the DNA or RNA
analytes are significantly reduced, making the molecules
more accessible to complementary PNA oligomers. Unlike
Fig. 9 Comparison of the structures of peptide nucleic acid (PNA) and
8 Chambers et al.
DNA, which depurinates at acidic conditions, PNAs are
stable across a wide range of temperatures and pHs.
Of significant importance in clinical samples, PNAs are
resistant to nucleases and proteases (Demidov et al.,
1994). In contrast to DNA molecular beacons, stemless
PNA beacons are less sensitive to ionic strength and the
quenched fluorescence of PNA is not affected by DNA-
binding proteins. This enables the use of PNA beacons
under conditions that are not feasible for DNA beacons.
The very different nature of PNA molecular structure
enables new modes of detection, especially procedures
that avoid the introduction of a label. Thus, the use of
PNAs will contribute significantly to establishment of
faster and more reliable biosensing applications. PNAs
have now been used to replace DNA to functionalize
gold nanoparticles (Chakrabarti and Klibanov, 200 ) and,
upon hybridization to complementary DNA strands and
formation of nanoparticle aggregates, resulted in (1) a
red-to-blue color transition and (2) high discrimination of
DNA single-base mismatches. The change of color results
from the shift of surface plasmon band (cf. aptamer based
recognition) upon aggregation and this property is now
the basis of colorimetric biosensors for selective detection
of DNA. PNA functionized gold nanoparticles have been
shown to be simple, highly sensitive and selective. Xi and
coworkers (Xi et al., 200 ) used DNA and PNA molecular
beacons to detect and quantify rRNA in solution and in
whole cells. Of clinical relevance, PNA molecular beacons
are ideal tools for detection of whole bacteria in solution
and in real time (Xi et al., 2005). Xi and coworkers use
real-time confocal microscopy to detect the fluorescence
emitted from DNA and PNA molecular beacons in
Molecular imprint based recognition
Molecular imprinting is a method for making selective
binding sites in synthetic polymers using molecular
templates. Molecular imprinted polymers offer great
promise for development of very stable “solid-state
like” artificial biosensing elements. In recent years, the
technology of molecular imprinting has proliferated as
an inexpensive, accessible and effective strategy for
developing sorbent materials exhibiting high specificity
for selected substrate materials. Shown in Fig. 10 is a
generalized scheme describing synthesis of a molecular
imprint receptor molecule. Although there are only a few
examples of molecular imprint recognition element based
biosensing, the possibility of imprinting against a wide
range of analytes raises the possibility of generation of
robust, artificial biological receptors making possible
multiple clinical sample analysis without pretreatment,
effectively reagentless chemistries. Molecular imprint-
quartz crystal microbalance detection is rapidly gaining
acceptance for transducing the presence of a variety
of analytes, especially glucose (Ersoz et al., 2005). Tai
and coworkers (2005) have demonstrated recognition of
Dengue viral protein using an epitope-mediated molecular
imprinted film. This is significant since rapid diagnosis of
this disease with high accuracy is crucial especially in
light of the current diagnostic methodologies that are time
and labor intensive and the lack of effective vaccines and
drugs for treatment.
Fig. 10 Schematic representation of the preparation of molecular
Lectin based recognition
Lectins constitute a broad family of proteins involved in
diverse biological processes, occasionally having potent
toxic properties. Lectins generally exhibit strong binding
to specific carbohydrate moieties known as glycans, and
this property has been extensively exploited as a basis
for biosensor design (Kim et al., 1990). Furthermore,
particular structural profiles of glycans and their recognition
by lectins have been attributed to disease progression,
making analysis of saccharide–lectin binding processes
important as a diagnostic tool.
Lectins are excellent biorecognition elements due
to high affinity for saccharide moieties via multivalent
interactions arising from the spatial organization of
oligosaccharide ligands. The selective binding of lectins
to terminal carbohydrate moieties on cell surfaces and
protein aggregates has been widely exploited (Bertozzi
and Kiessling, 2001). Although there are many ligand
specific lectins available for use as biosensor recognition
elements, Concanavalin A (Con A) is one of the most
widely used lectins for saccharide detection. Several
schemes entailing coupling of Con A to fluorescent
moieties have been employed for specific ligand detection
using fluorescence. Due to the high specificity of lectin
biorecognition elements, lectin based sensors have been
made which take advantage of advanced fluorescence
Biosensor Recognition Elements 9
techniques such as FRET. As with other biorecognition
elements, in the absence of bound saccharide ligand,
binding between the lectin and labeled carbohydrate target
allows high FRET efficiency. However, the fluorescence
energy transfer is decreased upon displacement of the
bound ligand by the carbohydrate analyte, thus facilitating
sensing of the soluble saccharide.
Lectin biorecognition elements have been used in
a number of biosensors including electrical-oscillation
(Yoshikawa and Omochi, 1986), piezoelectric crystal
oligosaccharide (Nagase et al., 200 ) and microcalorimetric
platforms (Gemeiner et al., 1998). An intriguing technique
for development of new and potentially important
sensors is based upon use of Langmuir–Blodgett
films of fullerene-glycodendron conjugates (Cardullo
et al., 1998). A novel saccharide “force fingerprinting”
technique based on single-molecule imaging capabilities
of Atomic Force Microscopy has been reported (Wong et
Discussion and conclusions
Despite the many technological advances in biosensor
recognition element development, the enzyme
biorecognition element mediated glucose sensor
dominates the current world market. The domination of
biorecognition by this one major analyte arises primarily
from the prevalence of diabetes in developed nations,
emphasizing further that biorecognition element based
sensing is expensive and must consider the development
costs and the size of the target market to be served.
In the coming decade, the ability to “recognize” and
“detect” electrically and magnetically will be radically
transformed. The emergence of magnetoelectronics is
a promising new platform technology for biorecognition
element/sensor development (Prinz, 1998). Although the
current prototypes have been directed at detection of
biological warfare agents of great strategic and clinical
relevance such as Bacillus anthracis, Yersinia pestis,
Brucella suis, Francisella tularensis, Vibrio cholerae,
Clostridium botulinum, Campylobacter jejuni and Vaccinia
virus, a first generation magnoresistive biorecognition
element based on spin valve sensors (Graham et al.,
2004) is now being developed for diagnostic biochip
detection of cystic fibrosis.
Nanotechnology is now making possible development
of in vivo sensors, i.e. nano-sized devices envisioned to
be ingested or injected where they could act as reporters
of in vivo concentrations of key analytes (LaVan et al.,
200 ). These engineered nanoparticle devices imbedded
in the cytosol of individual tissue specific cells will be
capable of transmitting recognition events, that is, the
binding to biorecognition elements of target analytes of
clinical relevance to an external data capture system.
Nanosensors will enable compartmental analyses of
metabolite levels and metabolic activity which will drive
“diagnostic methodologies.” Nanosensor prototypes
have been expressed in Yeast and in mammalian cell
cultures for determination of carbohydrate homeostasis
in living cells with subcellular resolution (Fehr et al.,
2005). Nanosensors can be selectively expressed under
the control of tissue specific promoters. The clinical
relevance arising from constant, real-time metabolic
vigilance via sensor based ligand specific biorecognition
elements is immense. Virus-based nanoparticles have
been developed for tumor specific recognition, targeting,
imaging and destruction.
Of particular note, DNA conjugate materials have
been prepared which can recognize DNA fragments with
one-base specificity (Sprintz, 2004) for reliable genotyping
of single nucleotide polymorphisms, while bacterial
magnetic particles have been integrated into functional
nanomaterials by assembling enzymes, antibodies and
receptors onto nano-sized bacterial magnetic particles
for use in applications such as determination of human
insulin (Sprintz, 2004).
The emerging ability to control patterns of matter on
the nanometer length scale can be expected to lead to
entirely new spatial positioning schemes of biorecognition
elements using a variety of new materials. Although current
technologies such as microstructure fabrication, surface
modification, integration of detection and optimization of
chemistry can not effectively complete with current, well-
established detection instrumentation, the need for high
throughput diagnostic/detection methods will continue.
If pursued, array technology should open the door for
commercializing sensor platforms utilizing a variety of
biorecognition elements for general diagnostic/detection
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