title: Design and synthesis of type-III mimetics of ShK toxin.
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.
authors.affiliation: Biomolecular Research Institute, Parkville, Victoria, Australia. jbaell@wehi.edu.au
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Harvey
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
mesh_terms: D000818:Animals; D001665:Binding Sites; D003064:Cnidarian Venoms / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D007166:Immunosuppressive Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D013816:Thermodynamics
chemical_list: D003064:Cnidarian Venoms; D007166:Immunosuppressive Agents; D026902:Potassium Channel Blockers; C095391:ShK neurotoxin