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Peptide hormones and signaling

How peptide hormones are made and act, and how drug designers make them last.

Key concepts

Peptide hormones are made as larger precursors (preprohormones) that are cut into active hormones in the secretory pathway. Insulin, for example, is cut from proinsulin, releasing C-peptide. They are stored in vesicles and released on demand.

Because they are water-soluble and too large to cross the cell membrane, peptide hormones bind cell-surface receptors:

• G protein-coupled receptors (GPCRs): for example GLP-1, glucagon, oxytocin, vasopressin and GnRH. They act through second messengers such as cAMP, calcium and IP₃/DAG.
• Receptor tyrosine kinases: for example the insulin receptor.

Why natural peptides make poor drugs

Natural peptide hormones often last only minutes in blood. Native GLP-1 is cut by the enzyme DPP-4 within about two minutes. Drug designers extend their life by:

• Swapping vulnerable amino acids, for example Aib in semaglutide.
• Adding a fatty-acid chain that binds albumin.
• Using D-amino acids, cyclization or C-terminal amidation (see octreotide).
• Fusing to antibody fragments, as in dulaglutide.

Timing matters too: pulsed GnRH stimulates reproductive hormones, while continuous exposure suppresses them, which is how leuprolide works.

Worked example

Common mistakes

• Thinking peptide hormones enter cells to act. Most act at the cell surface.
• Assuming peptides can simply be swallowed. Most are digested; oral semaglutide needs an absorption enhancer.
• Assuming more continuous hormone always means more effect. For GnRH it is the opposite.

Check yourself

Go deeper

• Nobel Prize 1977: hypothalamic peptide hormones
• VALREXA: Weight & metabolism peptides
• NCBI Bookshelf