Journal
FEBS LETTERS
Volume 594, Issue 17, Pages 2840-2866Publisher
WILEY
DOI: 10.1002/1873-3468.13855
Keywords
blood plasma; cerebrospinal fluid; peptide-drug stabilization; gamma 3-MSH-derived tag
Funding
- Interdisciplinary Research Grant of the Faculty of Biology and Medicine of the University of Lausanne
- Novartis Foundation for Biomedical Research Grant [14B062]
- Swiss National Science Foundation [310030_170108, 31003A_173178, 31003A_153467]
- Swiss National Science Foundation (SNF) [310030_170108, 31003A_173178, 31003A_153467] Funding Source: Swiss National Science Foundation (SNF)
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Bioactive peptide drugs hold promise for therapeutic application due to their high potency and selectivity but display short plasma half-life. Examination of selected naturally occurring peptide hormones derived from proteolytic cleavage of the proopiomelanocortin (POMC) precursor lead to the identification of significant plasma-stabilizing properties of a 12-amino acid serine-rich orphan sequence NSSSSGSSGAGQ in human gamma 3-melanocyte-stimulating hormone (MSH) that is homologous to previously discovered NS(n)GGH (n = 4-24) sequences in owls. Notably, transfer of this sequence to des-acetyl-alpha-MSH and the therapeutically relevant peptide hormones neurotensin and glucagon-like peptide-1 likewise enhance their plasma stability without affecting receptor signaling. The stabilizing effect of the sequence module is independent of plasma components, suggesting a direct effect incis. This natural sequence module may provide a possible strategy to enhance plasma stability, complementing existing methods of chemical modification.
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