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 ?M and 0.7 ?M, 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.

SUBMITTER: Chen R 

PROVIDER: S-EPMC4805292 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature