Genetically engineered two-warhead evasins provide a method to achieve precision targeting of disease-relevant chemokine subsets.

Abstract:

:Both CC and CXC-class chemokines drive inflammatory disease. Tick salivary chemokine-binding proteins (CKBPs), or evasins, specifically bind subsets of CC- or CXC-chemokines, and could precisely target disease-relevant chemokines. Here we have used yeast surface display to identify two tick evasins: a CC-CKBP, P1243 from Amblyomma americanum and a CXC-CKBP, P1156 from Ixodes ricinus. P1243 binds 11 CC-chemokines with Kd < 10 nM, and 10 CC-chemokines with Kd between 10 and 100 nM. P1156 binds two ELR + CXC-chemokines with Kd < 10 nM, and four ELR + CXC-chemokines with Kd between 10 and 100 nM. Both CKBPs neutralize chemokine activity with IC50 < 10 nM in cell migration assays. As both CC- and CXC-CKBP activities are desirable in a single agent, we have engineered "two-warhead" CKBPs to create single agents that bind and neutralize subsets of CC and CXC chemokines. These results show that tick evasins can be linked to create non-natural proteins that target subsets of CC and CXC chemokines. We suggest that "two-warhead" evasins, designed by matching the activities of parental evasins to CC and CXC chemokines expressed in disease, would achieve precision targeting of inflammatory disease-relevant chemokines by a single agent.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Alenazi Y,Singh K,Davies G,Eaton JRO,Elders P,Kawamura A,Bhattacharya S

doi

10.1038/s41598-018-24568-9

subject

Has Abstract

pub_date

2018-04-20 00:00:00

pages

6333

issue

1

issn

2045-2322

pii

10.1038/s41598-018-24568-9

journal_volume

8

pub_type

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