Peptide Pharmacology
FDA-Approved Peptide Drugs
| Drug | Sequence/Type | Indication | Route | Year |
|---|---|---|---|---|
| Insulin (Humulin) | 51 aa protein | Diabetes mellitus | SC injection | 1982 |
| Oxytocin (Pitocin) | Cys-Tyr-Ile-Gln-Asn-Cys-Pro-Leu-Gly-NH₂ | Labor induction | IV/IM | 1980 |
| Octreotide (Sandostatin) | D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol | Acromegaly, carcinoid | SC/IM | 1988 |
| Leuprolide (Lupron) | D-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt | Prostate cancer, endometriosis | IM depot | 1989 |
| Desmopressin (DDAVP) | Cys-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly-NH₂ | Diabetes insipidus | SC/IN | 1978 |
| Semaglutide (Ozempic) | GLP-1 analog (31 aa) | Type 2 diabetes, obesity | SC weekly | 2017 |
Pharmacokinetic Challenges
Proteolytic Instability
Peptides are degraded by endopeptidases and exopeptidases. Strategies: D-amino acid substitution, cyclization, PEGylation, fatty acid conjugation.
Poor Oral Bioavailability
Most peptides have F <2% orally. GI degradation, poor permeation, hepatic first-pass metabolism. Alternatives: nasal, pulmonary, transdermal, depot injections.
Short Half-Life
Typical t½ = 2-30 min for linear peptides. Extension strategies: albumin binding, Fc fusion, hyaluronic acid conjugation, microsphere depot.
Immunogenicity
Peptides can elicit anti-drug antibodies (ADA). Risk factors: sequence novelty, aggregation, immunostimulatory motifs. Monitoring: ADA assays, neutralizing antibody tests.
Drug Design Strategies
Modern peptide drug design leverages computational methods, structure-activity relationships (SAR), and innovative modification strategies to optimize potency, selectivity, and pharmacokinetic properties.
- Alanine scanning for hotspot identification
- Cyclization (head-to-tail, side chain-to-side chain)
- Stapled peptides for α-helix stabilization
- Peptide-drug conjugates (PDCs)
- Bicyclic peptides for enhanced target binding