title: Peptidomimetic Star Polymers for Targeting Biological Ion Channels.
abstract: Four end-functionalized star polymers that could attenuate the flow of ionic currents across biological ion channels were first de novo designed computationally, then synthesized and tested experimentally on mammalian K+ channels. The 4-arm ethylene glycol conjugate star polymers with lysine or a tripeptide attached to the end of each arm were specifically designed to mimic the action of scorpion toxins on K+ channels. Molecular dynamics simulations showed that the lysine side chain of the polymers physically occludes the pore of Kv1.3, a target for immuno-suppression therapy. Two of the compounds tested were potent inhibitors of Kv1.3. The dissociation constants of these two compounds were computed to be 0.1 μM and 0.7 μM, respectively, within 3-fold to the values derived from subsequent experiments. These results demonstrate the power of computational methods in molecular design and the potential of star polymers as a new infinitely modifiable platform for ion channel drug discovery.
authors.affiliation: Research School of Biology, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Derong
authors.initials: D
authors.lastname: Lu
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Zili
authors.initials: Z
authors.lastname: Xie
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Feng
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Zhongfan
authors.initials: Z
authors.lastname: Jia
authors.affiliation: ARC Centre of Excellence for Electromaterials Science, Research School of Chemistry, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Junming
authors.initials: J
authors.lastname: Ho
authors.affiliation: ARC Centre of Excellence for Electromaterials Science, Research School of Chemistry, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Coote
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, China.
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane QLD 4072, Australia.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Monteiro
authors.affiliation: Research School of Biology, Australian National University, Canberra ACT 2601, Australia.
authors.forename: Shin-Ho
authors.initials: SH
authors.lastname: Chung
mesh_terms: D018999:Charybdotoxin / Q000494:pharmacology; D004594:Electrophysiology; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D007473:Ion Channels / Q000187:drug effects*; D051664:Kv1.3 Potassium Channel / Q000187:drug effects; D057786:Peptidomimetics / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D007473:Ion Channels; D051664:Kv1.3 Potassium Channel; D057786:Peptidomimetics; D011108:Polymers; D015221:Potassium Channels; D018999:Charybdotoxin