Pharmacokinetic Investigation of a ¹⁴C‐Labelled β³/α Tetrapeptide in Rats

Abstract

The solid-phase synthesis and an ADME investigation with albino and pigmented male rats of the doubly 14C-labelled beta/alpha-tetrapeptide derivative Ac-beta3 hTyr-(D)Trp-beta3 hLys-beta3 hThr-lactone (3; Fig. 3) are described. After intravenous (i.v.) and peroral (p.o.) administration of the peptide, its concentration in blood and plasma, its tissue distribution, and the metabolism and the excretion of the peptide were analyzed over a period of up to 7 days post dose. The tetrapeptide in its ring opened form, 5, has a bioavailability of ca. 25%; radioactivity is distributed in the animals in an organ-specific way, and the compound appears to pass the blood-brain barrier to a very small extent, if at all (Tables 1-3 and Figs. 2-6). Excretion (37% renal, 44% fecal, including biliary) of the tetrapeptide 4 days after i.v. administration is almost complete, with only 4.3% remaining in the carcass; 4 days after p.o. administration 97% of the dose has been excreted in the feces. Radiochromatograms taken of plasma (0.5 and 24 h after i.v. dosing) and of urine and feces extracts (0-48 h collected) reveal the presence of lactone 3 and/or the corresponding hydroxy acid 5 with essentially no or very minor other peaks, respectively, representing possible metabolites (Tables 4-6, and Fig. 7 and 8). A comparison with a previous ADME investigation of a beta-nonapeptide show that--except for the lack of metabolism--all aspects of exposure, distribution, and elimination are different (structure-specific properties). The investigated tetrapeptide 3 is a potent and highly specific agonist of the somatostatin receptor hsst4, rendering the results described herein promising for diagnostic and therapeutic applications of beta-peptides.

The Proteolytic Stability of ‘Designed’β-Peptides Containingα-Peptide-Bond Mimics and of Mixedα,β-Peptides: Application to the Construction of MHC-Binding Peptides

“…In a similar fashion, mixed a,b 3 -tetrapeptide analogues of somatostatin can benefit from excellent binding affinities to the hsst 4 receptor, whilst retaining the complete proteolytic stability associated with the related pure b-tetrapeptidic compounds [13]. One such a,b 3 -tetrapeptide has been shown to be bioavailable when administered to rats [63].…”

Impact of Self-Assembly Properties on Antibacterial Activity of Short Acyl-Lysine Oligomers

“…Such structures can ideally circumvent the limitations imposed by the side chains of the 20 main naturally occurring ␣-amino acid building blocks. Furthermore, the artificial/modified backbone renders most peptidomimetics resistant to degradation enzymes, thereby increasing their stability in vivo (37,40,47). For the group with modified native backbones, several strategies were proposed, most of which are based on the preservation of a secondary structure similar to that of natural AMPs.…”

A Novel β-Peptidyl Aminopeptidase (BapA) from Strain 3-2W4 Cleaves Peptide Bonds of Synthetic β-Tri- and β-Dipeptides

“…Very detailed tests have shown that a variety of peptides composed of ␤-amino acids were stable against many different commercially available proteases and peptidases (10,29). Furthermore, first studies on the stability of ␤-peptides in vivo have shown that virtually no degradation was observed when such peptides were administered to rats (42,43). Some ␤-peptides possess antimicrobial activities (4,5,25,38), bind to the human somatostatin receptor (12,21), function as inhibitors of human immunodeficiency virus type 1 replication (39), and inhibit p53-hDM2 interaction (18).…”