Macrocyclic protease inhibitors with reduced peptide character

Area of Science:

• Medicinal Chemistry
• Structural Biology
• Biochemistry

Background:

• Beta-strand conformation is crucial for peptide-protein interactions, particularly in protease substrates and inhibitors.
• Existing peptide structures can be complex, necessitating simpler scaffolds for drug design.

Purpose of the Study:

• To design and synthesize simple, stable macrocyclic structures that define a beta-strand conformation.
• To develop potent protease inhibitors using these novel beta-strand templates.

Main Methods:

• Incorporation of a planar pyrrole ring to replace two amino acids in a peptide backbone, forming a macrocycle.
• Attachment of an amino aldehyde to the C-terminus of the pyrrole-containing macrocycle.
• Inhibition assays against cathepsin L and S proteases.
• X-ray crystallography to determine the binding mode with a model protease (chymotrypsin).

Main Results:

• Successful synthesis of macrocyclic beta-strand templates with reduced peptide character.
• Achieved picomolar inhibition potency against cathepsin L and cathepsin S.
• Elucidated the binding mode of a representative inhibitor to chymotrypsin via X-ray crystallography, confirming the defined geometry.

Conclusions:

• Pyrrole-based macrocycles effectively template beta-strand conformations for protease active site binding.
• These novel structures represent a promising scaffold for developing potent and specific protease inhibitors.
• Structural insights guide further optimization of these inhibitors for therapeutic applications.