Engineered Peptide Macrocycles Can Inhibit Matrix Metalloproteinases with High Selectivity

Area of Science:

• Biochemistry
• Molecular Biology
• Drug Discovery

Background:

• Matrix metalloproteinases (MMPs) are crucial enzymes involved in various physiological and pathological processes, including tissue repair, immunity, cancer, and inflammation.
• Developing selective small-molecule inhibitors for MMPs is challenging due to conserved structural features and shallow substrate-binding sites.

Purpose of the Study:

• To engineer a synthetic inhibitor targeting MMP-2 with high potency, selectivity, and stability.
• To demonstrate the feasibility of achieving selective MMP inhibition using peptide macrocycles.

Main Methods:

• Utilized a peptide engineering approach combining phage-display selections.
• Incorporated rational design for enhanced zinc chelation.
• Employed d-amino acid screening to improve proteolytic stability.

Main Results:

• Developed the first synthetic MMP-2 inhibitor with high potency (K_i =1.9±0.5 nm).
• Achieved high target selectivity and significant proteolytic stability.
• Demonstrated suitability for both in vitro and in vivo applications.

Conclusions:

• Selective MMP inhibition is attainable through peptide macrocycle engineering.
• The developed inhibitor serves as a valuable chemical probe and holds potential for therapeutic development.
• This work opens new avenues for designing specific MMP inhibitors.