Rapid Fire & Poster Presentation 7th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2019

A synthetic platform for the generation of anticoagulant sulfoprotein libraries (#18)

Emma E Watson 1 , Jorge Ripoll-Rozada 2 , Charlotte Franck 1 , Tim Pasch 1 , Bhavesh Premdjee 1 , Pedro J B Pereira 2 , Richard J Payne 1
  1. The University of Sydney, Sydney, NSW, Australia
  2. IBMC – Instituto de Biologia Molecular e Celular, Universidade do Porto, Porto, Portugal

Blood-feeding arthropods (such as ticks, mosquitoes and leeches) produce potent anti-coagulant proteins in their saliva to facilitate access to their blood meal. These compounds interfere with the coagulation cascade - a series of enzymes which regulate the process of blood clotting - particularly targeting the central enzyme of the cascade thrombin. Undesired blood clotting is implicated in several serious human diseases, including deep vein thrombosis and stroke, with thrombin inhibition representing a common therapeutic target.1 Using a bioinformatic approach, we have identified several proteins from blood-feeding organisms (including mosquitoes2 and ticks3) which not only possess potent thrombin inhibitory activity but which are modulated by post-translational tyrosine sulfation. Through a rapid, ligation-based platform we have gained access to a library of tick- and mosquito-derived sulfoproteins enabling us to probe the natural variance in potency amongst homologous proteins in a manner akin to small molecule medicinal chemistry. In this way we hope to exploit the innate anti-coagulant activities of these proteins and expedite their translation to elucidate pre-clinical anticoagulant leads.

  1. Lee, C. J. and Ansell, J. E. Direct thrombin inhibitors. British journal of clinical pharmacology 72, 581-592, (2011).
  2. Watson, E. E. et al. Mosquito derived Anophelin sulfoproteins are potent antithrombotics. ACS central science, 4, 468-476 (2018).
  3. Watson, E. E. et al. Rapid assembly and profiling of an anticoagulant sulfoprotein library. Proceedings of the National Academy of Sciences U.S.A., (doi:10.1073/pnas.1905177116).