Targeting dimerization of bax to modulate bax activity

Abstract

Methods are provided for identifying an agent that directly modulates a Bcl-2- associated x-protein (BAX) by promoting or disrupting dimerization of the BAX. Agents that directly modulate BAX by affecting dimerization are also provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Patent Application No. 62 / 005,013, filed on May 30, 2014, the contents of which are herein incorporated by reference in their entirety.STATEMENT OF GOVERNMENT INTEREST[0002]This invention was made with government support under grant number 5R00HL095929 awarded by the National Heart, Lung, and Blood Institute. The government has certain rights in this invention.BACKGROUND OF THE INVENTION[0003]Throughout this application various publications are referred to by number in parentheses. Full citations for these references may be found at the end of the specification. The disclosures of these publications, and all patents, patent application publications and books referred to herein, are hereby incorporated by reference in their entirety into the subject application to more fully describe the art to which the subject invention pertains.[0004]Programmed cell death, or apoptosis, is a fundam...

AI Technical Summary

Benefits of technology

The present invention provides methods for identifying agents that can interfere with or promote the dimerization of BAX, which is a protein involved in cell death. The invention also provides peptides that can modulate the activity of BAX and treat diseases associated with abnormal cell death. The technical effects of the invention include identifying new agents that can control cell death and potentially treating diseases associated with BAX.

Problems solved by technology

Dysregulation of apoptosis results in an imbalance of normal homeostasis contributing to diseases such as cancer and neurodegeneration (2,3).

Thus, inhibition of pro-apoptotic BAX or BAK impairs the cells' ability to initiate premature or unwanted cell death in terminally differentiated cells, including cardiomyocytes and neurons.

Despite remarkable progress in understanding BAX activation, current knowledge about the regulation mechanisms of BAX is limited.

However, there is no structural evidence or any mechanistic understanding of how cytosolic BAX is kept under control.

Although the early steps of BAX activation have been established, there is still a lack of understanding of the mechanisms that keep BAX under control in the cytosol and regulate its activation and translocation to the outer mitochondrial membrane.

However, there are currently no small molecule therapies that prevent or activate cell death through direct modulation of BAX's activity.

However, caspase inhibitors lack specificity among different caspases available in the cell, which is a liability for their successful clinical application.

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