Exenatide (revision 4)
Old revision·08:42, 20 Oct 2024·Retention_Time_Rae
| Exenatide | |
|---|---|
| INN | exenatide |
| Class | GLP-1 receptor agonist |
| Origin | Synthetic exendin-4 |
| First approval | 2005 |
| Compound infobox · conventions | |
Exenatide is a synthetic version of exendin-4, a 39-residue peptide isolated from the venom of the Gila monster, Heloderma suspectum. It shares approximately 53% sequence identity with human Glucagon-like peptide-1 and is a full agonist at the GLP-1 receptor. Approved in 2005, it was the first GLP-1 receptor agonist to reach the market.[1]
Its therapeutic relevance rests on an accident of sequence: exendin-4 carries glycine rather than alanine at position 2, so DPP-4 does not cleave it. No engineering was required to obtain protease resistance — the peptide is naturally resistant, and this is why a venom peptide became a diabetes drug.[1]
Origin and sequence
[edit]Exendin-4 was identified in Gila monster venom in the early 1990s and shown to bind the mammalian GLP-1 receptor with high affinity despite substantial sequence divergence. The peptide is not a lizard GLP-1 orthologue; lizards have their own GLP-1, and exendin-4 is a separate gene product expressed in the salivary gland.[1]
The C-terminal nine residues, absent from human GLP-1, form a tryptophan-cage motif that stabilises the helix and contributes to receptor affinity. This "Trp-cage" extension is the reason exendin-4 binds more tightly than native GLP-1 and is a frequently cited example of a natural product outperforming the endogenous ligand at its own receptor.