Journal article
Development of chemokine network inhibitors using combinatorial saturation mutagenesis
- Abstract:
- Targeting chemokine-driven inflammation has been elusive due to redundant pathways constituting chemokine-immune cell networks. Tick evasins overcome redundant pathways by broadly targeting either CC or CXC-chemokine classes. Recently identified evasin-derived peptides inhibiting both chemokine classes provide a starting point for developing agents with enhanced potency and breadth of action. Structure-guided and affinity maturation approaches to achieve this are unsuitable when multiple targets are concerned. Here we develop a combinatorial saturation mutagenesis optimisation strategy (CoSMOS). This identifies a combinatorially mutated evasin-derived peptide with significantly enhanced pIC50 against three different inflammatory disease chemokine pools. Using AlphaFold 3 to model peptide - chemokine interactions, we show that the combinatorially mutated peptide has increased total and hydrophobic inter-chain bonding via tryptophan residues and is predicted to sterically hinder chemokine interactions required for immune cell migration. We suggest that CoSMOS-generated promiscuous binding activities could target disease networks where structurally related proteins drive redundant signalling pathways.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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- Publisher copy:
- 10.1038/s42003-025-07778-6
Authors
+ Diabetes UK
More from this funder
- Funder identifier:
- https://ror.org/050rgn017
- Funding agency for:
- Bhattacharya, S
- Grant:
- 24/0006744
+ British Heart Foundation
More from this funder
- Funder identifier:
- https://ror.org/02wdwnk04
- Funding agency for:
- Bhattacharya, S
- Grant:
- CH/09/003/26631
- RG/F/23/110121
- RE/13/1/30181
- RG/18/1/33351
- Publisher:
- Nature Research
- Journal:
- Communications Biology More from this journal
- Volume:
- 8
- Issue:
- 1
- Article number:
- 549
- Publication date:
- 2025-04-03
- Acceptance date:
- 2025-02-19
- DOI:
- EISSN:
-
2399-3642
- Language:
-
English
- Pubs id:
-
2102035
- Local pid:
-
pubs:2102035
- Source identifiers:
-
W4409154226
- Deposit date:
-
2025-04-03
- ARK identifier:
Terms of use
- Copyright holder:
- Kryukova et al.
- Copyright date:
- 2025
- Rights statement:
- © The Author(s) 2025. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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