Harvard College

Health Research, Inc.

Daniel J Finley

Randall W King

Byung-Hoon Lee

Timothy Gahman

Min Jae Lee

Timothy C Gahman

Laura D Kramer

Nathaniel A Hathaway

Dilip Nag

John W Hanna

Proteinopathies result from the proteasome not acting efficiently enough to eliminate harmful proteins and prevent the formation of the pathogenic aggregates. As described herein, inhibition of proteasome-associated deubiquitinase Usp14 results in increased proteasome efficiency. The present invention therefore provides novel compositions and methods for inhibition of Usp14, enhancement of proteasome activity and treatment of proteinopathies.

Compositions and methods for enhancing proteasome activity

Tricyclic proteasome activity enhancing compounds

Disclosed herein are methods of treating or preventing a viral infection resulting from infection by a flavivirus, comprising administering to a subject a small molecule inhibitor of USP14, represented by Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, chemically-protected form, enantiomer or stereoisomer thereof, and pharmaceutical compositions comprising an effective amount of a compound of Formula (I) for use in the method. 

USP14 inhibitors for treating or preventing viral infections

This invention relates to methods and compositions for enhancing proteasome activity in a cell. The methods and compositions for enhancing the activity of the proteasome in cells modulate the activity of Ubp6 (yeast) or Usp14 (human), an endogenous inhibitor of the proteasome. The methods and compositions partially or completely reduce the inhibitory activity of Usp14 on a proteasome, thereby specifically enhancing the protein-degradation activity of the proteasome. The invention also provides methods of screening to identify inhibitors of Ubp6, Usp14, and/or both Ubp6 and Usp14.

Methods and compositions for enhancing proteasome activity

Growing community of inventors

Jamaica Plain, MA, United States of America

Daniel J Finley