1. A proopiomelanocortin-derived peptide sequence enhances plasma stability of peptide drugs.
- Author
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Löw K, Roulin A, and Kunz S
- Subjects
- Amino Acid Sequence, Cyclic AMP metabolism, Gene Expression, Glucagon-Like Peptide-1 Receptor blood, Glucagon-Like Peptide-1 Receptor genetics, HEK293 Cells, Humans, Melanocyte-Stimulating Hormones blood, Melanocyte-Stimulating Hormones genetics, Membrane Proteins blood, Membrane Proteins genetics, Peptides blood, Peptides chemical synthesis, Pro-Opiomelanocortin blood, Pro-Opiomelanocortin genetics, Protein Isoforms blood, Protein Isoforms chemistry, Protein Isoforms genetics, Protein Stability, Receptor, Melanocortin, Type 1 blood, Receptor, Melanocortin, Type 1 genetics, Receptors, Neurotensin blood, Receptors, Neurotensin genetics, Sequence Alignment, Sequence Homology, Amino Acid, Signal Transduction, Glucagon-Like Peptide-1 Receptor chemistry, Melanocyte-Stimulating Hormones chemistry, Membrane Proteins chemistry, Pro-Opiomelanocortin chemistry, Receptor, Melanocortin, Type 1 chemistry
- Abstract
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 γ3-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-α-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 in cis. This natural sequence module may provide a possible strategy to enhance plasma stability, complementing existing methods of chemical modification., (© 2020 Federation of European Biochemical Societies.)- Published
- 2020
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