Peptidomimetics bridge the gap between peptides and small-molecule drugs, combining the specificity of peptides with improved drug-like properties.
What Are Peptidomimetics?
Definition Molecules that mimic the structural and functional features of peptides while improving: - Metabolic stability - Membrane permeability - Oral bioavailability
The Goal Retain peptide-like **specificity and potency** while gaining small molecule-like **pharmacokinetics**.
Design Strategies
Backbone Modifications
- Block hydrogen bond donors
- Reduce protease recognition
- Increase lipophilicity
- Example: Cyclosporin A (7 N-methyl residues)
- Mirror images of natural amino acids
- Invisible to most proteases
- Example: D-Ser in semaglutide
- Side chain on nitrogen, not α-carbon
- No chiral center, no hydrogen bond donors
- Resist proteases completely
- Extra methylene in backbone
- Altered hydrogen bonding pattern
- Form stable 14-helix structures
Side Chain Modifications
- Expand chemical space
- Optimize binding interactions
- Example: Aib (α-aminoisobutyric acid)
- Restrict φ/ψ angles
- Pre-organize structure
- Reduce entropic cost of binding
Amide Bond Isosteres
| Isostere | Properties |
|---|---|
| -CH₂-NH- (reduced) | Flexible, stable |
| -CO-N(CH₃)- | N-methylated |
| -CS-NH- (thioamide) | Protease resistant |
| Triazole | Click chemistry product |
| E-alkene | Rigid, non-polar |
Stapled Peptides
Concept Covalent cross-links that lock peptide into α-helical conformation
Chemistry - Olefin-containing amino acids at i, i+4 or i, i+7 - Ring-closing metathesis (RCM) forms hydrocarbon bridge - Results in all-hydrocarbon "staple"
Advantages 1. **Structural stability** — Pre-organized for binding 2. **Protease resistance** — Backbone protected 3. **Cell permeability** — Can enter cells 4. **Intracellular targets** — Access PPIs
Clinical Development **ALRN-6924:** - Stapled p53 peptide - Inhibits MDM2 and MDMX - Reactivates p53 tumor suppressor - Phase 1/2 clinical trials
Cyclic Peptides
Natural Examples | Peptide | Size | Source | Use | |---------|------|--------|-----| | Cyclosporin A | 11 AA | Fungus | Immunosuppression | | Vancomycin | 7 AA | Bacteria | Antibiotic | | Daptomycin | 13 AA | Bacteria | Antibiotic |
Advantages of Cyclization - Reduced conformational flexibility - Improved protease resistance - Enhanced membrane permeability - Better oral bioavailability
Cyclization Strategies - **Head-to-tail** — N to C connection - **Disulfide** — Cysteine cross-link - **Lactam** — Side chain to backbone - **Thioether** — Cys to dehydroalanine
Macrocyclic Peptides
Display Technologies - **mRNA display** — In vitro selection - **Phage display** — Bacterial amplification - **SICLOPPS** — Intein-mediated cyclization
Natural Product-Inspired - Combine peptide with non-peptide elements - "Peptide-small molecule hybrids" - Expand chemical space
Success Stories
| Drug | Type | Target | Indication |
|---|---|---|---|
| Cyclosporin A | Cyclic, N-methylated | Cyclophilin | Immunosuppression |
| Semaglutide | D-AA, Aib, lipidated | GLP-1R | Diabetes, obesity |
| Romidepsin | Cyclic depsipeptide | HDAC | Cancer |
| Pasireotide | Cyclized somatostatin | SSTR | Cushing's disease |