Synthesis of Sulfated Peptides Derived from Evasin Proteins from Ticks reveals Unique Biomimetic Binding to Chemokines — ASN Events
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  3. Synthesis of Sulfated Peptides Derived from Evasin Proteins from Ticks reveals Unique Biomimetic Binding to Chemokines

Synthesis of Sulfated Peptides Derived from Evasin Proteins from Ticks reveals Unique Biomimetic Binding to Chemokines (#212)

Anthony Ayoub 1 2 , Charlotte Franck 1 2 , Richard Payne 1 2
  1. School of Chemistry, The University of Sydney, Sydney
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney

Upon tissue damage and infection, a functional immune system recruits leukocytes through a process called chemotaxis that involves chemokines signaling through chemokine receptors. Chemokine binding and subsequent signaling is dependent on a two-site binding model with cognate chemokine G-protein coupled receptors (GPCRs). However, the dysregulated recruitment of these chemokines plays a significant role in the pathology of various inflammatory and autoimmune diseases. As such, chemokines and their receptors serve as valuable therapeutic targets for the modulation of these disease pathways.

A significant step in the binding of chemokines with cognate receptors is the electrostatic interaction of an electropositive patch on chemokine proteins with N-terminal sulfated tyrosine (sTyr) residues on receptors, which provides an increase in binding affinity. 1, 2 This interaction is crucial for activity, such that it served as an evolutionary target for protein biomimicry by hematophagous organisms to inhibit the host immune response whilst obtaining a blood meal. 3-5 An example of this is the evasin family, salivary proteins derived from ticks, that utilize N-terminal sTyr to bind to chemokine proteins in order to inhibit cognate receptor binding and hence downstream immune signaling through chemokine receptor mimicry. 6-8

These sulfated biomolecules are privileged starting points for the development of effective therapeutics against inflammatory and autoimmune disease as evolution has adapted them for successful modulation of host defenses. 4 As such, a reliable understanding of their binding and interaction with chemokines is essential. These first steps were recently explored via the semi synthesis of full-length evasin protein, ACA-01, 3, 9, 10 which provided essential structure-activity data. 11 In this presentation, we will further explore this by utilizing solid-phase peptide synthesis (SPPS) to synthesize N-terminal sTyr peptides derived from evasin proteins in order to further uncover novel and modulated binding of chemokine proteins.

  1. Stone, M. J.; Hayward, J. A.; Huang, C.; E Huma, Z.; Sanchez, J. Mechanisms of Regulation of the Chemokine-Receptor Network. Int. J. Mol. Sci. 2017, 18 (2), 342.
  2. Bannert , N.; Craig , S.; Farzan , M.; Sogah , D.; Santo , N. V.; Choe , H.; Sodroski , J. Sialylated O-Glycans and Sulfated Tyrosines in the NH2-Terminal Domain of CC Chemokine Receptor 5 Contribute to High Affinity Binding of Chemokines. J. Exp. Med. 2001, 194 (11), 1661-1674.
  3. Bhusal, R. P.; Eaton, J. R. O.; Chowdhury, S. T.; Power, C. A.; Proudfoot, A. E. I.; Stone, M. J.; Bhattacharya, S. Evasins: Tick Salivary Proteins that Inhibit Mammalian Chemokines. TIBS. 2020, 45 (2), 108-122.
  4. Bonvin, P.; Power, C. A.; Proudfoot, A. E. I. Evasins: Therapeutic Potential of a New Family of Chemokine-Binding Proteins from Ticks. Front. Immunol. 2016, 7 (208).
  5. Déruaz, M.; Frauenschuh, A.; Alessandri, A. L.; Dias, J. M.; Coelho, F. M.; Russo, R. C.; Ferreira, B. R.; Graham, G. J.; Shaw, J. P.; Wells, T. N. C.; et al. Ticks produce highly selective chemokine binding proteins with antiinflammatory activity. J. Exp. Med. 2008, 205 (9), 2019-2031.
  6. Stone, M. J.; Payne, R. J. Homogeneous Sulfopeptides and Sulfoproteins: Synthetic Approaches and Applications To Characterize the Effects of Tyrosine Sulfation on Biochemical Function. Acc. Chem. Res. 2015, 48 (8), 2251-2261.
  7. Ludeman, J. P.; Stone, M. J. The structural role of receptor tyrosine sulfation in chemokine recognition. Br. J. Pharmacol. 2014, 171 (5), 1167-1179.
  8. Dias, J. M.; Losberger, C.; Déruaz, M.; Power, C. A.; Proudfoot, A. E. I.; Shaw, J. P. Structural Basis of Chemokine Sequestration by a Tick Chemokine Binding Protein: The Crystal Structure of the Complex between Evasin-1 and CCL3. PLOS ONE 2010, 4 (12), e8514.
  9. Hayward, J.; Sanchez, J.; Perry, A.; Huang, C.; Valle, M. R.; Canals, M.; Payne, R. J.; Stone, M. J. Correction: Ticks from diverse genera encode chemokine-inhibitory evasin proteins. JBC 2018, 293 (41), 15888.
  10. 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. 2017, 7 (1), 4267.
  11. Franck, C.; Foster, S. R.; Johansen-Leete, J.; Chowdhury, S.; Cielesh, M.; Bhusal, R. P.; Mackay, J. P.; Larance, M.; Stone, M. J.; Payne, R. J. Semisynthesis of an evasin from tick saliva reveals a critical role of tyrosine sulfation for chemokine binding and inhibition. PNAS. 2020, 117 (23), 12657-12664.
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