Stabilized Analogs of Thymopentin. 1. 4,5-Ketomethylene Pseudopeptides

Abstract

The pentapeptide, thymopentin (Arg1-Lys2-Asp3-Val4-Tyr5) is known for its activity as an immunomodulating drug, but with limited half-life in plasma. In this first paper of a series of three studies, the synthesis of analogs stabilized at the peptide bond between the C-terminal amino acids via insertion of a ketomethylene moiety is described. N-Blocked pseudopeptides containing Val(k)Phe, Ala(k)Phe, and Val(k)Val units were prepared and attached to chloromethyl Merrifield resin via the carboxy terminal. Removal of the N-BOC group by trifluoroacetic acid was followed by sequential coupling with N-BOC dipeptides of aspartic acid to yield resin-bound N-BOC pseudotetrapeptides. Removal of N-BOC and coupling with N-BOC-r-N-tosylarginine followed by total cleavage of blocking groups and resin by HF afforded the target pseudopentapeptides. The analogs were found to compete favorably with thymopentin for binding to CEM cells, but binding was reduced by about 20-30% on average. All analogs showed significant enhancement of half-life versus thymopentin in mouse serum, but most showed only modest improvement in human serum. Insertion of proline or norleucine at position 2 in the chain caused a substantial increase in half-life (3-4-fold), while N-methylnorleucine conferred complete stability in the analogs.

Design and Development of a Novel Peptide for Treating Intestinal Inflammation

“…Native anti-inflammatory peptides are a class of anti-inflammatory agents that may be useful in the treatment of a range of inflammatory diseases (13, 18, 25). However, several concerns, such as potential cytotoxicity (35), poor anti-inflammatory activity based on peptide concentration, and weak physiological stability (57), have weakened their development as anti-inflammatory therapeutics. Hybridizing different anti-inflammatory peptides is one of the most successful approaches to obtain a novel anti-inflammatory peptide with increased activity but minimized cytotoxicity (58, 59).…”

A Novel Peptide Ameliorates LPS-Induced Intestinal Inflammation and Mucosal Barrier Damage via Its Antioxidant and Antiendotoxin Effects

“…Recently, native anti-inflammatory peptides, such as LL-37 and TP5, have shown enormous potential in the treatment of a range of inflammatory diseases [27,28,42]. However, several obstacles, including potential cytotoxicity [29], poor anti-inflammatory activity based on peptide concentration, and weak physiological stability [43], reduce their clinical potential.…”

“…Considering the short half-life of TP5 in plasma, repeated injections and a long treatment duration are necessary to improve clinical efficacy [43]. Thus, it was important to prolong the half-life of the peptide.…”

Chemical Synthesis and Application of C-Terminally 5-Carboxyfluorescein-labelled Thymopentin as a Fluorescent Probe for Thymopoietin Receptor

“…10,20 In addition, acetylation in the N-terminus and/or racemization of Arg at position 1 also reduced the receptorbinding activity. 14 With respect to the C-terminus, substitution at position 5, such as Val, His, and Trp, gave biologically active analogues, and a number of substitutions were also tolerated at position 4.…”