NF-?B is a ubiquitous transcription factor responsible for expression of genes that regulate processes including inflammation, cell proliferation, and cell differentiation. However, the misregulation of the NF-?B signaling pathway found in chronic inflammatory diseases and metastatic cancers is often the result of constitutive activation of the NF-?B pathway. A key regulator of the NF-?B signaling pathway is the multi-subunit IKK complex made up of IKK a/� and NF-?B essential modifier (NEMO, IKK?). A pre-requisite for IKK activity and subsequent NF-?B activation requires dimerization of the NEMO N-terminal domain, which provides two binding sites for the C-terminus of IKK a/� to bind and results in an active tetrameric complex. It has previously been demonstrated that inhibiting assembly of this tetrameric complex can inhibit activation of the NF-?B signaling pathway, highlighting the importance of inhibitors that can target assembly of this complex.The C-terminal ends of IKK a/� responsible for binding to NEMO are highly conserved. It has been previously demonstrated that a six-amino acid sequence (L737DWSWL742) within IKK a/� is crucial for IKK complex formation. Additionally, when a cell-permeable peptide is appended to this NEMO binding peptide (NBD), it can inhibit NF-?B activation. However, inhibition of NF-?B activity with NBD is modest (IC50 >100 �M), likely due to proteolytic instability. Herein, we describe a peptidomimetic strategy using �stapled� peptide technology to inhibit NF-?B activity. Through incorporation of two olefins into the NBD sequence, ring-closing metathesis was used to generate a constrained peptide. This constrained peptide demonstrates greater potency and efficacy compared to the unmodified NBD for inhibition of NF-?B activation. Furthermore, this constrained peptide represents a new strategy for inhibiting the assembly of the IKK complex that has not previously been explored.

Inhibiting the NF-?B IKK complex using a stapled peptide

248th National Meeting (2014)

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