Exenatide (revision 18)
Old revision·13:15, 17 Jun 2025·CiteBot
| ExenatideClinical data | |
|---|---|
| INN | exenatide |
| Class | GLP-1 receptor agonist |
| Origin | Synthetic exendin-4 |
| First approval | 2005 |
| Properties | |
| Residues | 39 |
| Molar mass | 4,186.6 g·mol⁻¹ |
| Half-life, immediate release | ≈2.4 h |
| Half-life, extended release | ≈2 weeks apparent |
| 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]
Two formulations were marketed: a twice-daily immediate-release product, and a once-weekly extended-release product in which the peptide is encapsulated in poly(lactide-co-glycolide) microspheres. Both have been largely displaced by later agents with greater efficacy and simpler pharmacokinetics.[2]
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.
Glycine at position 2 provides the DPP-4 resistance. The resulting half-life of about 2.4 hours is still short — renal clearance dominates once proteolysis is removed — which is why the immediate-release product required twice-daily injection.
As a 39-residue synthetic peptide, exenatide is characterised by the ordinary battery for a synthetic peptide drug substance — chromatographic purity, peptide content, water, counterion and related substances — rather than by the protein methods needed for a fusion construct.[3]
The extended-release formulation
[edit]The weekly product suspends exenatide in biodegradable poly(lactide-co-glycolide) microspheres, which release peptide as the polymer hydrolyses. This is a formulation solution to a pharmacokinetic problem rather than a molecular one, and it behaves differently from a long-half-life molecule.[2]
Concentrations rise slowly over six to seven weeks to a plateau, so the full effect of starting treatment is not seen for around two months, and concentrations decay over a comparable period after stopping. Neither the onset nor the offset can be accelerated. A distinctive injection-site nodule occurs in a substantial minority of recipients, attributable to the polymer matrix rather than to the peptide.
The suspension also requires reconstitution and vigorous mixing immediately before injection, a preparation burden that later single-solution products removed.
See also
References
- ^ a b c Nielsen LL, Young AA, Parkes DG. "Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes." Regulatory Peptides 117(2):77–88 (2004). PMID 14700743.
- ^ a b Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). PMID 29617641.
- ^ United States Pharmacopeia, General Chapter <1503>, Quality Attributes of Synthetic Peptide Drug Substances.