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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

microfluidic systems.

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

al., 2002).

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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James P. Chambers1,*, Bernard P. Arulanandam1, Leann L. Matta2, Alex Weis3, and James J. Valdes4 iconJames P. McCulley, md, Chair

James P. Chambers1,*, Bernard P. Arulanandam1, Leann L. Matta2, Alex Weis3, and James J. Valdes4 icon20: 04: 19 James Jacobs joins Main

James P. Chambers1,*, Bernard P. Arulanandam1, Leann L. Matta2, Alex Weis3, and James J. Valdes4 iconJames f. Peters, csr, rpr

James P. Chambers1,*, Bernard P. Arulanandam1, Leann L. Matta2, Alex Weis3, and James J. Valdes4 iconKenneth Conboy and James Morrison

James P. Chambers1,*, Bernard P. Arulanandam1, Leann L. Matta2, Alex Weis3, and James J. Valdes4 iconZach Eastman James Haschmann

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