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Engineered anti-inflammatory peptides inspired by mapping an evasin-chemokine interaction.
Benoit Darlot1, James R O Eaton1,2, Lucia Geis-Asteggiante1
1Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford, United Kingdom.
The Journal of Biological Chemistry
|May 31, 2020
Summary
Researchers developed novel anti-inflammatory peptides from tick evasins to target chemokine networks. These peptides effectively block inflammation in preclinical models, offering a promising therapeutic strategy for inflammatory diseases.
Area of Science:
- Immunology
- Biochemistry
- Medicinal Chemistry
Background:
- Chemokines are crucial for immune cell function but their complex networks pose therapeutic challenges for inflammatory diseases.
- Tick salivary evasins offer a potential solution by binding multiple chemokines, yet clinical translation is hindered by immunogenicity and cost concerns.
- Peptide-based therapeutics can overcome limitations associated with protein-based drugs.
Purpose of the Study:
- To develop novel peptide-based therapeutics that mimic the multi-chemokine binding and anti-inflammatory properties of evasins.
- To identify and characterize the specific binding interface of evasin P672 with C-C motif chemokine ligand (CCL) 8.
- To create and validate peptide derivatives with enhanced chemokine-binding and anti-inflammatory efficacy.
Main Methods:
- Hydrogen-deuterium exchange mass spectrometry (HDX-MS) to map evasin-chemokine binding interfaces.
- Peptide synthesis based on identified binding regions.
- Biophysical assays (fluorescence polarization, native MS, isothermal titration calorimetry) to characterize peptide-chemokine interactions.
- In vitro chemotaxis assays and in vivo inflammation models to assess functional efficacy.
Main Results:
- A 16-mer peptide (BK1.1) was synthesized based on the P672-CCL8 binding interface, demonstrating binding to CCL8, CCL7, and CCL18, and disruption of CCL8 homodimerization.
- A derivative peptide (BK1.3) showed enhanced disruption of P672 binding to CCL8, CCL2, and CCL3, and directly bound CCL8.
- BK1.3 effectively inhibited the chemotactic function of multiple chemokines in vitro and potently blocked inflammation in vivo via local and systemic administration.
Conclusions:
- The chemokine-binding interface of evasins can be leveraged to design potent anti-inflammatory peptides.
- Peptide BK1.3 exhibits broad chemokine-binding and anti-inflammatory activity, representing a promising therapeutic candidate for inflammatory diseases.
- This approach offers a novel strategy to therapeutically target robust chemokine networks in conditions like atherosclerosis and autoimmune diseases.
