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

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.

Tumor Necrosis Factor-α Trimer Disassembly and Inactivation via Peptide-Small Molecule Synergy.

Aberrant signaling by tumor necrosis factor-α (TNFα) is associated with inflammatory diseases that can be treated with engineered proteins that inhibit binding of this cytokine to cell-surface receptors. Despite these clinical successes, there is considerable interest in the development of smaller antagonists of TNFα-receptor interactions. We describe a new 29-residue α/β-peptide, a molecule that contains three β-amino acid residues and three α-aminoisobutryic acid (Aib) residues, that displays potent inhibition of TNFα binding to TNFα receptor 1 (TNFR1) and rescues cells from TNFα-induced death.

Differential Effects of β - versus β -Amino Acid Residues on the Helicity and Recognition Properties of Bim BH3-Derived α/β-Peptides.

Oligomers containing α- and β-amino acid residues (α/β-peptides) have been shown to mimic the α-helical conformation of conventional peptides when the unnatural residues are derived from β -amino acids or cyclic β-amino acids, but the impact of incorporating β residues has received little attention. The effects of β residues on the conformation and recognition behavior of α/β-peptides that mimic an isolated α-helix were investigated. This effort has focused on 26-mers based on the Bim BH3 domain; a set of isomers with identical α/β backbones that differ only in the placement of certain side chains along the backbone (β vs.

α/β-Peptide Foldamers Targeting Intracellular Protein-Protein Interactions with Activity in Living Cells.

Peptides can be developed as effective antagonists of protein-protein interactions, but conventional peptides (i.e., oligomers of l-α-amino acids) suffer from significant limitations in vivo.

Introduction of cyclically constrained γ-residues stabilizes an α-peptide hairpin in aqueous solution.

The synthesis and structural characterization of hybrid α/γ-peptides resulting from a 1:1 α→γ residue substitution at cross-strand positions in a hairpin-forming α-peptide sequence are described. Cyclically constrained γ-residues based on 1,3-substituted cyclohexane or benzene scaffolds support a native-like hairpin fold in aqueous solution, and the unnatural residues stabilize the folded state by ∼0.2 kcal/mol per α→γ substitution.