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Strategies to Enhance Metabolic Stabilities
Bhavesh Khatri1, Venkateswara Rao Nuthakki1, Jayanta Chatterjee2
1Molecular Biophysics Unit, Indian Institute of Science, Bangalore, India.
Methods in Molecular Biology (Clifton, N.J.)
|May 29, 2019
Summary
Macrocyclic peptides offer unique structural benefits for drug discovery but face metabolic instability. Enhancing their conformational rigidity through chemical or biological methods improves stability and efficacy by slowing protease cleavage.
Area of Science:
- Medicinal Chemistry
- Drug Discovery
- Biochemistry
Background:
- Macrocyclic peptides possess constrained backbones, enabling defined 3-D pharmacophore orientation.
- Despite conformational advantages for lead discovery, their peptide bonds are prone to proteolytic degradation in biological settings, limiting therapeutic use.
Purpose of the Study:
- To review chemical and biological strategies for enhancing the metabolic stability of macrocyclic peptides.
- To highlight how conformational rigidity impacts protease resistance and overall efficacy.
Main Methods:
- Review of classical and contemporary chemical modification techniques.
- Analysis of biological approaches to improve peptide stability.
- Assessment of structure-stability relationships in macrocyclic peptides.
Main Results:
- Chemical modifications can impart local or global conformational rigidity to macrocyclic peptides.
- Increased rigidity correlates with reduced susceptibility to proteolytic cleavage.
- Strategies discussed aim to overcome metabolic liabilities inherent in peptide-based therapeutics.
Conclusions:
- Modulating the conformational rigidity of macrocyclic peptides is a key strategy to enhance their metabolic stability.
- Improved stability translates to better therapeutic potential for macrocyclic peptide drugs.
- Further research into chemical and biological stabilization techniques is warranted.
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