Subunit-selective nucleic acid inhibitors of glutamate receptors

US9200286B2 · kind B2 · utility

Assignee

• The Research Foundation for The State University of New York · US

Inventors

• Li Niu · Loudonville, US
• Zhen Huang · Brooklyn, US
• Jae Seon Park · Seoul, KR

Key dates

• Filing date: Jul 15, 2011
• Grant date: Dec 1, 2015
• Expiry date: Jul 15, 2031

Classification

• Technology area (CPC C): Chemistry; Metallurgy
• CPC primary: C12N2320/13
• WIPO field: Biotechnology
• WIPO sector: Chemistry

Abstract

Inhibitors of AMPA-type glutamate ion channels are useful as biochemical probes for structure-function studies and as drug candidates for a number of neurological disorders and diseases. Disclosed herein is the identification of an RNA inhibitor or aptamer by an in vitro evolution approach and characterization of its mechanism of inhibition on the sites of interaction by equilibrium binding and on the receptor channel-opening rate by a laser-pulse photolysis technique. The aptamer of the invention is a noncompetitive inhibitor of AMPA-type glutamate ion channels, one that selectively inhibits the GluA2Qflip AMPA receptor subunit without any effect on other AMPA receptor subunits or on kainate or NMDA receptors. Furthermore, the aptamer preferentially inhibits the closed-channel state of GluA2Qflip with a KI=1.5 μM or by ˜15-fold over the open-channel state. The potency and selectivity of this aptamer rival those of small molecule inhibitors. Together, these properties make the aptamers of the present invention promising water-soluble, highly potent, GluA2 subunit-selective drugs.