Peptidomimetics and Peptide Engineering

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

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