Targeting cardiac inflammation in post-infarction myocardial injury using novel chemokine-ligand traps derived from tick saliva

Oxford

£20,474

2016

We have, with a previous CRM grant, identified several novel anti-chemokine compounds called evasins from tick saliva. The project ambitions were to a) obtain further in vitro IC50 and in vivo dose & safety data for these evasins; b) Evaluate evasin efficacy in post MI injury. These studies should provide proof-of-concept that our evasins are potential therapeutics in MI.  We have performed extensive in vitro biophysical/ biochemical (e.g. affinity for chemokines) and cell biological characterization (e.g. IC50 data for inhibition of cell migration) of a number of evasins through this grant funding, and these are reported in the papers listed. The preliminary data generated, together with the first pump priming award, led to external grants including a BHF Program Award. Moreover, we have created improved, two warhead and multi-warhead evasins that extend the capacity of evasins to target both CC and CXC chemokines. We were unable to perform in vivo studies in myocardial infarction due to limitations at the CRM core facility, but after discussion with the CRM director Professor Paul Riley, we decided that myocardial infarction studies would be better performed in a 3 year project where two and multi-warhead evasins would be investigated; this project has been funded from CRM2, in which evasins are a major translational deliverable.

1. Singh, K., Davies, G., Alenazi, Y., Eaton, J.R.O., Kawamura, A. & Bhattacharya, S. Yeast surface display identifies a family of evasins from ticks with novel polyvalent CC chemokine-binding activities. Sci Rep 7, 4267 (2017).

2. Eaton, J.R.O., Alenazi, Y., Singh, K., Davies, G., Geis-Asteggiante, L., Kessler, B., Robinson, C.V., Kawamura, A. & Bhattacharya, S. The N-terminal domain of a tick evasin is critical for chemokine binding and neutralization and confers specific binding activity to other evasins. J Biol Chem 293, 6134-6146 (2018).

3. Alenazi, Y., Singh, K., Davies, G., Eaton, J.R.O., Elders, P., Kawamura, A. & Bhattacharya, S. Genetically engineered two-warhead evasins provide a method to achieve precision targeting of disease-relevant chemokine subsets. Sci Rep 8, 6333 (2018).