The Arora and Zhang Groups describe design of a protein tertiary structure mimic to target Kaposi’s sarcoma herpesviral oncoprotein. The study was performed in collaboration with researchers at Weill Cornell Medical College and describes a compound that suppresses NF-κB signaling and delays tumor growth in a PEL xenograft model. NYU Chemistry contributors include first author Michael Wuo (currently a postdoc at MIT), David Rooklin (currently CEO of Redesign Science), Seong Ho "Johnny" Hong, Paramjit Arora and Yingkai Zhang.
Read the article in Nature Communications: Modulation of virus-induced NF-κB signaling by NEMO coiled coil mimics
Abstract: 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.
This research was supported by the National Institutes of Health and the Leukemia and Lymphoma Society.