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Peptide Drug Discovery: Perspectives in Design, Development and Delivery

BY: Debasis Sahu | Category: Biotechnology-products | Submitted: 2010-11-10 17:56:32
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Article Summary: "Drug designing and development using suitable synthetic and natural peptides has been proved to be a promising field of drug discovery. The basis for choosing peptide is the one or more number of sequences which may be the parts of the target proteins. These peptides may be responsible for molecular recognition and other biologi.."

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Drug designing and development using suitable synthetic and natural peptides has been proved to be a promising field of drug discovery. The basis for choosing peptide is the one or more number of sequences, which may be the parts of the target proteins. These peptides may be responsible for molecular recognition and other biological processes. The main objectives of this field include the designing of peptides in such as way that it will inhibit the protein-protein interactions and to mimic the small molecule inhibitors of the target proteins as ligands. The targeted mode of action makes the peptides as an ideal candidate for drug development.

To look for a peptide mimetic, it is very important to identify a peptide or a peptide sequence within the target protein that is considered for the assay. Structural constraints are considered to look for the validity of the features.

Interaction between peptide and the biological target, which may be protein or nucleic acid, occurs by direct binding of the sequence to a number of conformations of the target. Approaches including modern peptide mimetics make use of the small molecules formation, which simulate peptides to overcome their insuffciency to act as drugs with oral administration. Instead, the small molecular mimetics have the required biological effects of the peptide lead, also are stable with huge diversity; they can be designed to produce novel drugs.

Prospects of peptide drugs: With enhanced technologies, the prospects of the peptide drugs are getting increased and clearer, day-by-day. Three main developments have been found to be responsible. Firstly, several peptides and hormones have been discovered and have found applications in biopharmaceuticals with newly developed analytical techniques. Secondly, industrial-scale production of proteins and polypeptides has been possible by genetic engineering and molecular biology techniques. Finally, a better functional conception of regulatory peptides and proteins in the pathophysiology of several human diseases has been achieved.

Peptide synthesis is done mainly by two established methods , which include

Liquid-phase synthesis is a conventional technique for the synthesis of peptides. Now-a-days, it is getting replaced with solid-phase synthesis because of its ease as compared to the former. However, liquid phase synthesis remains useful in the large-scale production of peptides for industrial purposes.

Solid-phase synthesis or solid-phase peptide synthesis (SPPS) facilitates the synthesis of natural peptides difficult to be synthesized by recombinant DNA techniques, modification of peptide backbone, the synthetic amino acid incorporation, and D-protein synthesis.

Advantages of peptide drugs:
Small peptides as drug are very specific in nature. Also, peptide drugs pose other advantages over therapeutic proteins, owing to their higher solubility, better stability, more bio-availability and negligible immune response.

Limitations of peptide drugs:
Instability of peptide is due to the proteolytic cleavage of the peptide backbone.

Low bioavailability of the peptides is also a major drawback associated with peptide drugs which is partly due to the poor membrane transport capability of its amide backbone structure.

Awkward route of administration: Peptide drugs have been administered generally through injections in the blood stream which is generally unacceptable to the patients. Polypeptide drug delivery designing and formulating has been a persistent challenge because of their unfavorable physicochemical properties, which includes enzymatic degradation, poor membrane permeability and large molecular size.

Strategies to overcome limitations:

Progress in biotechnology and gene technology helped in the development of a numerous potential therapeutic polypeptides in industrial scale.
List of several pharmaceutical approaches that are available for maximizing oral protein and peptide absorption:

Chemical modification of peptide and protein drugs increases their stability and/or the chances of their membrane permeability, also may be used for minimizing immunogenicity. These modifications are done either by modification of exposed amino acid side-chains of proteins or in the glycan part of glycoproteins.

Enzyme inhibitors: Protease inhibitors are chosen according to the structure of the drugs, and the specificity of the former is necessary for the drug stability in the GI tract.

Absorption enhancers are the components which temporarily disturb the intestinal barrier to enhance the drug permeabilization.

Formulation vehicles help to surmount the barriers of luminal proteases and acid, in the GI tract, many formulation strategies are being tested like the use of microspheres, liposomes, enteric-coated dry emulsions, and nanoparticles for delivery of the peptide drugs through oral route.

To conclude, oral delivery of peptides drugs is extremely difficult objective. Digestive system is likely to cleave the peptides prior to assimilation. Solution to the low bioavailability of such drugs remains to be developed.
Moreover, the establishment of a peptide lead to an end user drug is extremely challenging and long process.

About Author / Additional Info:
Written by Debasis Sahu and Shikha Sharma

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