Trimer-to-Monomer Disruption Mechanism for a Potent, Protease-Resistant Antagonist of Tumor Necrosis Factor-α Signaling.

Jiani Niu, Annika J Cederstrand, Geoffrey A Eddinger, Boyu Yin, James W Checco, Craig A Bingman, Victor K Outlaw, Samuel H Gellman

Journal of the American Chemical Society 2022 Jun 08

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Aberrant tumor necrosis factor-α (TNFα) signaling is associated with many inflammatory diseases. The homotrimeric quaternary structure of TNFα is essential for receptor recognition and signal transduction. Previously, we described an engineered α/β-peptide inhibitor that potently suppresses TNFα activity and resists proteolysis. Here, we present structural evidence that both the α/β-peptide inhibitor and an all-α analogue bind to a monomeric form of TNFα. Calorimetry data support a 1:1 inhibitor/TNFα stoichiometry in solution. In contrast, previous cocrystal structures involving peptide or small-molecule inhibitors have shown the antagonists engaging a TNFα dimer. The structural data reveal why our inhibitors favor monomeric TNFα. Previous efforts to block TNFα-induced cell death with peptide inhibitors revealed that surfactant additives to the assay conditions cause a more rapid manifestation of inhibitory activity than is observed in the absence of additives. We attributed this effect to a loose surfactant TNFα association that lowers the barrier to trimer dissociation. Here, we used the new structural data to design peptide inhibitors bearing a surfactant-inspired appendage intended to facilitate TNFα trimer dissociation. The appendage modified the time course of protection from cell death.

Citation

Jiani Niu, Annika J Cederstrand, Geoffrey A Eddinger, Boyu Yin, James W Checco, Craig A Bingman, Victor K Outlaw, Samuel H Gellman. Trimer-to-Monomer Disruption Mechanism for a Potent, Protease-Resistant Antagonist of Tumor Necrosis Factor-α Signaling. Journal of the American Chemical Society. 2022 Jun 08;144(22):9610-9617