Poster Presentation 8th Venoms to Drugs 2023

Structure–activity relationships of tst2: a novel trpv1 inhibitory peptide from the Australian sea anemone telmatactis stephensoni (#110)

Renad Albar 1 , Khaled Elnahriry 1 , Dorothy Wai 1 , Lauren Ashwood 2 , Muhammad Naseem 3 , Tibor Szanto 3 , Gyorgy Panyi 3 , Peter Prentis 2 4 , Ray Norton 1 5
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
  2. School of Biology and Environmental Science, Faculty of Science, Queensland University of Technology, Brisbane, QLD 4000, Australia
  3. Department of Biophysics and Cell biology, Faculty of Medicine, University of Debrecen, 4032, Debrecen, Hungary
  4. Centre for Agriculture and the Bioeconomy, Queensland University of Technology, Brisbane, QLD 4000, Australia
  5. ARC Centre for Fragment-Based Design, Monash University, Parkville, Victoria 3052, Australia

Sea anemones are a rich source of peptide toxins known to display a diverse range of biological activities, especially targeting membrane proteins such as ion channels, receptors and transporters. These peptide toxins and their analogues are typically highly stable and selective for their molecular targets. This enables the investigation of their potential as molecular tools, insecticides, and therapeutics [1]. Recent transcriptomic and proteomic analyses of the sea anemone Telmatactis stephensoni identified a novel 38-residue peptide, designated Tst2 [2]. We determined the solution structure of Tst2 based on NMR data [3], revealing that it adopts an inhibitor cystine knot (ICK) structural motif [4]. The biological activity profile of Tst2 was assessed against various ion channels using electrophysiological assays. Tst2 showed > 50% inhibition of the transient receptor potential subfamily V member 1 (TRPV1) at 100 nM [3]. This relatively potent TRPV1 inhibitor may therefore be an interesting lead for the development of novel analgesics and anti-inflammatory drugs. We are currently exploring the structure-activity relationship of Tst2 to identify the key residues for TRPV1 inhibition.

  1. Prentis, P. J.; Pavasovic, A.; Norton, R. S. Sea Anemones: Quiet Achievers in the Field of Peptide Toxins. Toxins (Basel) 2018, 10.
  2. Ashwood, L. M.; Undheim, E. A. B.; Madio, B.; Hamilton, B. R.; Daly, M.; Hurwood, D. A.; King, G. F.; Prentis, P. J. Venoms for all occasions: The functional toxin profiles of different anatomical regions in sea anemones are related to their ecological function. Mol Ecol 2022, 31, 866-883.
  3. Elnahriry, K. A.; Wai, D. C. C.; Ashwood, L. M.; Naseem, M. U.; Szanto, T. G.; Panyi, G.; Prentis, P. J.; Norton, R. S. Structural and functional characterisation of Tst2, a novel TRPV1 inhibitory peptide from the Australian sea anemone Telmatactis stephensoni. 2023, (submitted).
  4. Pallaghy, P. K.; Nielsen, K. J.; Craik, D. J.; Norton, R. S. A common structural motif incorporating a cystine knot and a triple-stranded β-sheet in toxic and inhibitory polypeptides. Protein Sci 1994, 3, 1833-9.