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Design and synthesis of type-III mimetics of ShK toxin

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Abstract

ShK toxin is a structurally defined, 35-residue polypeptide which blocks the voltage-gated Kv1.3 potassium channel in T-lymphocytes and has been identified as a possible immunosuppressant. Our interest lies in the rational design and synthesis of type-III mimetics of protein and polypeptide structure and function. ShK toxin is a challenging target for mimetic design as its binding epitope consists of relatively weakly binding residues, some of which are discontinuous. We discuss here our investigations into the design and synthesis of 1st generation, small molecule mimetics of ShK toxin and highlight any principles relevant to the generic design of type-III mimetics of continuous and discontinuous binding epitopes. We complement our approach with attempted pharmacophore-based database mining.

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Author notes

  1. Jonathan B. Baell

    Present address: The Walter and Eliza Hall Institute of Medical Research, Royal Parade, Parkville, Victoria, Australia, 3050

Authors and Affiliations

  1. Biomolecular Research Institute, 343 Royal Parade, Parkville, Victoria, Australia

    Jonathan B. Baell, Andrew J. Harvey & Raymond S. Norton

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  1. Jonathan B. Baell
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  2. Andrew J. Harvey
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  3. Raymond S. Norton
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Correspondence to Jonathan B. Baell.

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Baell, J.B., Harvey, A.J. & Norton, R.S. Design and synthesis of type-III mimetics of ShK toxin. J Comput Aided Mol Des 16, 245–262 (2002). https://doi.org/10.1023/A:1020214720560

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