Macrocyclic Modalities Combining Peptide Epitopes and Natural Product Fragments

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biochemistry

Background:

• "Hot loop" protein segments are crucial for protein-protein interactions due to their variable structure.
• Mimicking these dynamic regions is challenging but essential for drug discovery.

Purpose of the Study:

• To introduce a novel modality, PepNats, for creating conformationally constrained mimics of protein "hot loops".
• To synthesize and characterize PepNats derived from inducible nitric oxide synthase (iNOS) and human agouti-related protein (AGRP) hot loops.
• To evaluate the binding affinity and selectivity of these PepNats to their respective biological targets.

Main Methods:

• Incorporation of natural product (NP)-inspired structures into macrocyclic peptides.
• Solid-phase synthesis utilizing macrocyclization by imine formation.
• Stereoselective 1,3-dipolar cycloaddition for conformational constraint.

Main Results:

• Successfully synthesized macrocyclic PepNats from iNOS and AGRP hot loops.
• PepNats derived from iNOS showed potent ligand activity for SPRY domain-containing SOCS box protein 2 (SPSB2).
• PepNats derived from AGRP exhibited selective ligand activity for melanocortin (MC) receptors.

Conclusions:

• The absolute configuration of NP-inspired fragments dictates the peptide conformation and binding properties.
• Combining NP scaffolds with peptidic epitopes yields effective hot loop mimics.
• PepNats represent a promising strategy for developing conformationally constrained peptides with therapeutic potential.