Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics

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作者：
Jouliana Sadek
Michael G. Wuo
David Rooklin
Arthur Hauenstein
Seong Ho Hong
Archana Gautam
Hao Wu
Yingkai Zhang
Ethel Cesarman
Paramjit S. Arora
机构：
[1] Weill Cornell Medical College,Department of Pathology and Laboratory Medicine
[2] New York University,Department of Chemistry
[3] Harvard Medical School,Department of Biological Chemistry and Molecular Pharmacology
[4] Icahn School of Medicine at Mount Sinai,NYU
[5] New York University−Shanghai,ECNU Center for Computational Chemistry
来源：
Nature Communications | / 11卷
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摘要：
Protein-protein interactions featuring intricate binding epitopes remain challenging targets for synthetic inhibitors. Interactions of NEMO, a scaffolding protein central to NF-κB signaling, exemplify this challenge. Various regulators are known to interact with different coiled coil regions of NEMO, but the topological complexity of this protein has limited inhibitor design. We undertook a comprehensive effort to block the interaction between vFLIP, a Kaposi’s sarcoma herpesviral oncoprotein, and NEMO using small molecule screening and rational design. Our efforts reveal that a tertiary protein structure mimic of NEMO is necessary for potent inhibition. The rationally designed mimic engages vFLIP directly causing complex disruption, protein degradation and suppression of NF-κB signaling in primary effusion lymphoma (PEL). NEMO mimic treatment induces cell death and delays tumor growth in a PEL xenograft model. Our studies with this inhibitor reveal the critical nexus of signaling complex stability in the regulation of NF-κB by a viral oncoprotein.
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