Peptide and protein degradation

Goolcharran C, Khossravi M, Borchardt RT. Chemical pathways of peptide and protein Degradation. In Frokjaer S, Hovgaard L, eds. Pharmaceutical Formulation Development of Peptides and Proteins. (Pharmaceutical Science.) U.K. Taylor and Francis, 1999. 

A number of reactions of amino acids have become important in recent years because they are essential to the degradation, sequencing, and chemical synthesis of peptides and proteins. These reactions are discussed in Chapter 5. 

Peptide and protein drugs must be transported without metabolic degradation to the systemic circulation in order to exhibit or exert their pharmacological action. Although active transport of linear peptides and oligopeptides by intestinal oligopeptide transporters has been reported, overall intestinal absorption of peptides is very poor because of metabolic degradation by peptidases. " ... 

Synthesis and degradation of cychns Peptide and protein synthesis Protein kinase reactions Mitosis... 

With all of the advances in polymer science and conjugation technology, many methods have been developed to increase the feasibility of oral peptide and protein delivery. There is still no single mechanism that can be used to protect a protein or peptide from degradation and increasing oral availability, but with the multitude of new methods for allowing a protein to negotiate natural barriers, oral delivery of any systemically active protein is a definite possibility at some point in the future. 

JL Glajch, JJ Kirkland, J Kohler. Effect of column degradation on the reversed-phase high-performance liquid-chromatographic separation of peptides and proteins. J Chromatogr 384 81-90, 1987. 

The formation of methyl- (MTH) or phenylthiohydantoin (PTH) amino acids is a valuable technique for sequencing of amino acids in peptides and proteins by the Edman degradation procedure [1], HPLC is very useful for the separation of MTH- or PTH-amino acids as adsorption [2,3], reversed-phase [4] and ion-exchange [S] chromatography. 

As mentioned above, the rectal route is very attractive for systemic delivery of peptide and protein drugs, but rectal administration of peptides often results in very low bioavailability due to not only poor membrane penetration characteristics (transport barrier) but also due to hydrolysis of peptides by digestive enzymes of the GI tract (enzymatic barrier). Of these two barriers, the latter is of greater importance for certain unstable small peptides, as these peptides, unless they have been degraded by various proteases, can be transported across the intestinal membrane. Therefore, the use of protease inhibitors is one of the most promising approaches to overcome the delivery problems of these peptides and proteins. Many compounds have been used as protease inhibitors for improving the stability of various peptides and proteins. These include aprotinin, trypsin inhibitors, bacitracin, puromycin, bestatin, and bile salts such as NaCC and are frequently used with absorption enhancers for improvement in rectal absorption. 

To improve the absorption of peptides and proteins, the employment of different enzymatic inhibitors has been suggested. For example, some authors have demonstrated the usefulness of inhibitors of both exo- and endopeptidases to promote calcitonin absorption across rat vaginal mucosa [93]. A direct relationship was found between the effect of peptidase inhibitors of in vitro degradation constant of calcitonin in vaginal mucosa homogenates and in vivo promotion of drug absorption, indicated by the decrease in plasma calcium levels after calcitonin administration in rats. The peptidase inhibitors tested were pepstatin, bestatin, and leupeptin. 

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