Myristic acid-modified thymopentin for enhanced plasma stability and immune-modulating activity

•TP5-MA increases the albumin binding affinity.•TP5-MA exhibits enhanced stability in human plasma.•TP5-MA preserves the bioactivities in RAW 264.7 mouse macrophages.•TP5-MA improves the pharmacokinetic properties in rats.•TP5-MA prolongs immune-modulating effects in immune-depressed rats.

Natural albumin ligand (fatty acids)-conjugated peptides can rapidly bind to circulating albumin and form complexes to control the release of peptides. The purpose of this study was to prolong the half-life and immune-modulating effects of thymopentin (TP5) by using the albumin binding strategy. We synthesized myristic acid-modified TP5 (TP5-MA) by conjugating a myristic acid-acylated lysine to a permissive site of TP5, which improved the albumin binding affinity of TP5-MA and dramatically enhanced its stability in human plasma. We observed well-preserved bioactivities of TP5-MA in RAW264.7 macrophages using a tumor necrosis factor (TNF)-α stimulation assay. Moreover, the prolonged immune-modulating effect of TP5-MA was confirmed by the normalized CD4+/CD8+ ratio in immune-depressed rat models, which resulted in a reduced administration frequency (twice per week). In general, the enhanced pharmacokinetic and pharmacodynamic properties of TP5-MA make it a promising product for the treatment of immunodeficiency diseases.

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