Peptide peptidase-resistant

Structure-activity relationship studies with cyclic or unnatural peptides to enhance activity and peptidase resistance. 

Niven, R.W., F. Rypacek, and P.R. Byron. 1990. Solute absorption from the airways ofthe isolated rat lung. III. Absorption of several peptidase-resistant, synthetic polypeptides poly-(2-hydroxyethyl) -as-partamides. Pharm. Res. 7 990-994. Hoover, J.L., B.D. Rush, K.F. Wilkinson, J.S. Day, P.S. Burton,T.J. Vidmar, and M.J. Ruwart. 1992. Peptides are better absorbed from the lung than the gut in the rat. Pharm. Res. 9 1103-1106. 

There does not appear to be any significant proteolytic degradation by enzymes in the extracellular fluid in normal human airways and alveoli. However, the presence of peptidases makes absorption of small peptides variable and difficult to predict. Peptidase-resistant peptides generally show better bioavailabilities than other peptides with comparable molecular weights. ° Difference in metabolism and absorption of d and L forms of peptides glycyl-D-phenylalanine and glycyl-L-phenylalanine was demonstrated by Morimoto et al.f The l peptide was subject to metabolism, and it had significant paracellular transport with a smaller transcellular component. In contrast, the... 

With the objective to improve the transport and the peptidase resistance of peptides, we have been engaged in the synthesis of the peptide-scaffold hybrids. In the course of our longstanding interest on these molecules, we have prepared a panoply of... 

Alternate ways to interfere with the orexin system may be via inhibition of dipeptidyl peptidases or proteolysis-resistant peptide analogs as shown for other peptides. This could prolong and boost orexinergic signaling. OX-A but not OX-B can enters the brain by simple diffusion via the blood-brain barrier. Abundance of orexins and their receptors in the olfactory bulb and throughout all parts of the central olfactory system may offer transnasal routes for drug application. 

The proteolytic activity of some multicatalytic peptidases is stimulated by ATP, whereas that of others is not influenced by ATP [32], The ATP-dependent proteolytic system first found in reticulocytes requires the presence of a heat-stable polypeptide called ubiquitin, one of the roles of which is to mark particular proteins for subsequent degradation [33. ATP-Indepen-dent multicatalytic peptidases can degrade proteins that have a free amino or an /V-acctylatcd terminus, as well as oxidatively altered or phosphorylat-ed proteins [34], The small peptides generated are resistant to multicatalytic peptidases and are further degraded by cytoplasmic endopeptidases and exopeptidases. 

The lability of host defense peptides to proteases and peptidases has been investigated as a method for increasing the therapeutic efficacy of these molecules. The high concentration of basic residues in host defense peptides increases the lability of these molecules to endogenous trypsin-like enzymes and represents a significant therapeutic impediment. As host defense peptides are significantly sensitive to proteases, with half-lives of minutes in vivo, peptides that are protease resistant while retaining activity would offer a potential resolution to this problem. 

Asn-Pro, Asp-Met, Asp-Leu, Ala-Val, and Gly-Val were isolated from fermented sardine sauce further, the ACE-inhibitory peptides Ala-Pro, Arg-Pro, Gly-Pro, and Ala-Gly-Pro were isolated from fermented bonito sauce. Val-Pro was also identified in salted and fermented anchovy by Lee (1996). Among the peptides identified by Ichimura et al. (2003), Ala-Pro, Lys-Pro, and Arg-Pro showed strong and similar inhibitory activity. Ichimura et al. (2003) also isolated nine types of peptides containing Pro residues in their carboxy terminals. Due to the unique structure of Pro as an imino acid, peptide bonds containing Pro residues are often resistant to hydrolysis by common peptidases. This may be the reason why these Pro-containing dipeptides survived after long-term fermentation. Among these peptides, Lys-Pro was further evaluated in vivo in male SHRs (Charles River Japan, Yokohama) by oral administration. As shown in Fig. 5.3, orally administered Lys-Pro shows a tendency to lower the blood pressure of SHRs. 

Probably the most important protective mechanisms involve the tripeptide GSH (chap. 4, Fig. 59). This compound is found in most cells, and in liver cells, it occurs at a relatively high concentration, about 5 mM or more. There are three pools of GSH cytosolic, mitochondrial, and nuclear. GSH structure is unusual for a peptide in the glutamyl, and cysteine residues are not coupled via a peptide bond, hence the molecule is resistance to peptidase attack. It has a nucleophilic thiol group, and it can detoxify substances in one of three ways ... 

It is well known that the incorporation or substitution of a D-tryptophan residue into a biologically active peptide chain enhances the activity of that chain. Furthermore, such incorporation or substitution will prolong the biological activity. The prolonged and enhanced effectiveness of such peptides probably relates the increased resistance to degradation by peptidases. 

Glycosylation has also been reported to improve intestinal absorption of peptide drugs which demonstrate poor membrane penetrability. For instance, glycosylation at the /V-terminus of tetrapeptide (Gly-Gly-Tyr-Arg) increases its resistance to degradation by peptidases in addition, Na+-dependent glucose transporters were shown to play an important role in the intestinal absorption of both /)-(succinylamido)phenyl a- or p-D-ghicopyranosides (Nomoto et al. 1998). 

As described in Section 1.6.1 exopeptidases cleave at N- and C-termini and include aminopeptidases, carboxypeptidases and dipeptidyl peptidase, whereas endopeptidases cleave at an internal peptide bond and include enkephalinase and cathepsin B. Small peptides are relatively resistant to the action of endopeptidases but their activity is significant for large peptides. 

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