Peptidomimetic star polymers for targeting biological ion channels

Date

2016

Authors

Chen, Rong
Lu, Derong
Xie, Zili
Feng, Jing
Jia, Zhongfan
Ho, Junming
Coote, Michelle
Wu, Yingliang
Monteiro, Michael J
Chung, Shin-Ho

Journal Title

Journal ISSN

Volume Title

Publisher

Public Library of Science

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.

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Citation

Source

PLOS ONE (Public Library of Science)

Type

Journal article

Book Title

Entity type

Access Statement

Open Access

License Rights

DOI

10.1371/journal.pone.0152169

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