Peptides metabolic instability

The first reported selective inhibitors of the HATs p300 and PCAF were peptides representing structurally simple bi-substrate analogs of H3 and acetyl-CoA [10, 11]. Hence, p300 was inhibited by Lys-CoA 1 and the more specific PCAF by the 20-amino-acid peptide H3-CoA-20 2 (Figure 11.2). Unfortunately, these inhibitors showed low cell permeability and high metabolic instability, which decreases their suitability for investigations in vivo [12]. 

The potential utility of peptides as therapeutic agents with clinical applications is limited as a consequence of intrinsic peptide properties such as metabolic instability or poor transmembrane mobility. Hence, the design and synthesis of meta-bolically stable peptide analogs that can either mimic or block the bioactivity of natural peptides or enzymes is an important area of medicinal chemistry research. Numerous structural modifications to peptides have been examined in pursuit of molecules with more desirable properties [1-3]. These modified structures, peptidomimetics, are nonpeptide molecules that imitate the desired properties of the natural substances. 

Fig. 6.4. Chemical, metabolic, and physical processes of instability in pharmaceutical peptides...

The cellular effects of FTase inhibition with 3 were observed with concentrations 5000-50,000 higher than the in vitro IC50 for FTase inhibition by carboxylic acid Id. Incomplete hydrolysis of the lactone in vivo could be partially responsible for this discrepancy in activity. However, it was also found that the lactone prodrug used in the context of the doubly reduced peptide isostere, i.e. 3, was chemically unstable at physiological pH. Rapid cyclization to the diketopiperazine 5 significantly reduced FTase inhibitory activity.40 Simple N-alkylation of the reactive secondary amine to give 4 led to loss of activity vs. FTase. To simultaneously protect the compound from both metabolic inactivation (via peptidases) and chemical instability, isosteric replacements of the second amide bond other than methylene-amino were explored. Since the second amide bond in the tetrapeptide inhibitors could be reduced without loss of activity in vitro, peptide bond replacements which were both rigid (olefin) and flexible (alkyl, ether) were synthesized. 

Local metabolism in the nose and instability of compound (especially for peptide drugs). 

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