Oral Presentation 8th Venoms to Drugs 2023

The interaction of peptide toxins with the voltage-gated potassium channel KV1.3: role of conformational dynamics (#5)

Karoline Sanches 1 2 , Lauren M. Ashwood 3 , Abisola A.O. Siedoks 1 , Dorothy C.C. Wai 1 , Arfatur Rahman 1 , Kashmala Shakeel 4 , Muhammad U. Naseem 4 , Gyorgy Panyi 4 , Peter J. Prentis 3 5 , Ray S. Norton 1 2
  1. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Victoria, Australia
  2. ARC Centre for Fragment-Based Design, Melbourne, Victoria, Australia
  3. School of Biology and Environmental Science, Queensland University of Technology, Brisbane, Queensland , Australia
  4. Department of Biophysics and Cell Biology, University of Debrecen, Debrecen, Hajdú-Bihar, Hungary
  5. Centre for Agriculture and the Bioeconomy, Queensland University of Technology, Brisbane, Queensland , Australia

The ShKT is a common scaffold in sea anemone peptides, first found in a toxin from Stichodactyla helianthus.1 The ShK-186 (Dalazatide), an ShK analogue, has completed Phase 1 clinical trials to treat plaque psoriasis.2 Although the ShKT are found in numerous species, only a tiny fraction have been functionally characterised, with some ShKT peptides from sea anemones inhibiting KV1.x, others do not.3, 4 The KV1.x blockade is mediated by a Lys-Tyr (KY) dyad, but other cationic followed by a hydrophobic residue may also be relevant, but not necessarily guarantee their activity to block those ion channels.5 In this work, we used NMR and MD simulations to predict the potential activity of the novel ShKT peptide, the ShKT-Ts1. We solved the 3D solution structure of ShKT-Ts1 and performed functional essays against a range of KV1.x channels. Although ShKT-Ts1 has an ShK-like fold and a Lys-Phe dyad, it does not show significant activity against KV1.x channels. With MD simulations, we investigated whether solvent exposure of the dyad residues may be informative in rationalising and potentially predicting the ability of ShKT peptides to block KV1.x channels. We propose a relationship between the extent of solvent exposure of the dyad, peptide dynamics and activity against KV1.x, with channel-blocking activity depending on the exposure of the dyad. The presence of buried or partially exposed dyads that are buried during MD simulations correlates with weak or absent activity against KV1.x channels. Therefore, structure prediction, coupled with MD simulations, can be used to predict whether new sequences belonging to the ShKT family may act as potassium channel blockers.

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