Peptide stability

Formation of helical-like peptides stabilized due to heterocyclic bridges formed between coils by natural and artificial amino acids 99T11711. 

Stabilizers bind at a site separate from those of traditional activators and of ciguatoxin-brevetoxin, but they exert a synergistic action on both types of activators (J5, 42). This action potentiates the activators and generally increases their efficacy, yielding larger depolarizations at lower doses 42) it occurs uniquely with the peptide stabilizers and not with ions or oxidants that also slow the inactivation of Na current 37). 

Y. J. Wang and M. A. Hanson, Parenteral formulations of proteins and peptides Stability and stabilizers. 

The addition of PEG to the gels was critical because the PEG chains participate in the macromolecular complexes, function as a peptide stabilizer and enhance the mucoadhesive characteristics of the gels. In this work, strong dose-dependent hypoglycemic effects were observed in healthy and diabetic rats following oral administration of these gels. 

We now turn briefly to the problem of peptide stability in the solid state [8] [88], First, we note that most - if not all - reactions discussed in the previous and subsequent sections can also occur in the solid state, although the kinetics and mechanisms of the reactions can be quite different from those observed in solution. Moisture content, the presence of excipients that act as catalysts, and surface phenomena are all factors whose roles are all-but-im-possible to predict. As a result, each formulation poses a new challenge to pharmaceutical scientists. As a rule, solution data cannot be used to predict the shelf-life of solid formulations, and extrapolating from one solid formulation to another can be misleading. 

Peptide stability in solids has been briefly presented in Sect. 63.2.5. It is important to note here that deamidation reactions can also play a major role in the degradation of peptides in solid matrixes. While deamidation in the solid state has received less attention than deamidation in solution, there is enough evidence to suggest that the mechanisms and pathways are comparable if not similar in the two types of media [8] [130],... 

With continuous development of systems for controlled drug release, new materials are being used whose influence on peptide stability must be carefully examined. Thus, the model hexapeptide Val-Tyr-Pro-Asn-Gly-Ala (Fig. 6.30) embedded in poly (vinyl alcohol) and poly(vinyl pyrrolidone) matrices had rates of deamidation that increased with increasing water content or water activity, and, hence, with decreasing glass transition temperature (Tg). However, the degradation behavior in the two polymers differed so that chemical reactivity could not be predicted from water content, water activity, or T% alone. Furthermore, the hexapeptide was less stable in such hydrated polymeric matrices than in aqueous buffer or lyophilized polymer-free powders [132],... 

A number of observations converge to indicate that much of plasma peptidase activity is due to aminopeptidases, with A-protection markedly increasing peptide stability in blood. Dipeptidyl-peptidase is another noteworthy peptidase in blood. In human plasma, some of the peptides showed very small tm values of only a few minutes, but a majority of f1/2 values were on the order of 10-30 min. 

M. F. Powell, Peptide Stability in Drug Development In vitro Peptide Degradation in Plasma and Serum , Annu. Rep. Med. Chem. 1993, 28, 285-294 M. F. Powell, H. Grey, F. Gaeta, A. Sette, S. Colon, Peptide Stability in Drug Development a Comparison of Peptide Reactivity in Different Biological Media , J. Pharm. Sci. 1992, 81, 731-735. 

Fig. 4. Illustration of an a-helical peptide stabilized by a transition metal complex involving two histidine or one histidine and one cysteine side chains. (Reprodnced with the permission of Ref. 7)...

Based on very similar principles, though more recently, Suzuki and Fujii (1999) designed a helix-loop-helix peptide. On a related theme, the aforementioned design from Pandya et al. (2004) for a helix-loop-helix peptide stabilized by a disulfide bridge used similar ideas, although the final sequence was very different from the Myszka and Chaiken and the Suzuki and Fujii peptides, as it was also made compatible with a parallel coiled-coil dimer to promote conformational switching. 

Powell, M.F., Stewart, T., Otvos, L., Jr., et al. (1993) Peptide stability in drug development. II. Effect of single amino acid substitution and glycosylation on peptide reactivity in human serum. Pharmacol. Res. 10, 1268-1273. 

Synthetic peptides often lack the conformational stability required for a successful drug therefore determination of peptide stability in serum constitutes a powerful and important screening assay for the elimination of unstable peptides in the pipeline of drug development (see Note 1). Peptide stability in serum can rather easily be determined by reverse phase-high-performance liquid chromatography (RP-HPLC) and mass spectroscopy (MS) from both in vitro and in vivo studies. 

In Vitro Peptide Stability in Serum/Reaction Kinetics... 

In Vivo Peptide Stability Assay/Pharmacokinetics in Mice... 

In vivo testing of peptide stability is obviously of more relevance than in vitro testing. However, a better term would probably be peptide pharmacokinetics (in mice), given that these measurements basically are also done in vitro. 

Stevenson, C. L. (2000), Characterization of protein and peptide stability and solubility in non-aqueous solvents, Curr. Pharm. Biotechnol., 1,165-182. 

Early SAR investigations revealed that the amide of Met-enkephalin was several times as active as the parent with a longer duration of action and that replacement of Gly2 by D-Ala had a similar influence on peptide stability/62,63 It was later shown that a variety of D-amino acids in place of Gly2 caused a marked increase in potency both in GPI and MVD assays, results presumed... 

The 1-125 protein column (operated in a normal-phase mode) was chosen as the final purification step for two reasons 1) the small (sometimes invisible) amount of residue remaining after the previous purification steps was easily dissolved in 95% acetonitrile 5% water (the initial-conditions solvent for this system) and 2) the peaks collected from this column were in a solution (75%-85% acetonitrile) suitable for peptide stabilization and required no further manipulation (other than capping) prior to storage. The structures of the 11 myotropic cockroach peptides isolated with this method are listed, along with appropriate references, in Table I (leucokinins... 

Table 1 Summary of amino acid and peptide stabilized nanoparticles...

Figure 2 Biomimetic synthesis strategy for peptide encapsulated nanoclusters. Synthesis begins with complexation of peptide hgand to metal ion, followed by borohydride reduction of metal complex, nucleation, and formation of peptide stabilized nanocluster. (Reprinted with permission from Ref. 1. 2003 American Chemical Society)...

Brunelle P, Schoneich C, Rank A. (2006) One-electron oxidation of methionine peptides — Stability of the three-electron S-N(amide) bond. Can J Chem 84 893-904. 

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