Stapled Peptides.

Stapled Peptides are peptide mimics useful for the modulation of protein and receptor signaling and subsequent gene expression. These designed stapled peptides bind specifically to proteins such as cytokines, protein hormones, and nuclear hormone receptors and offer an alternative approach to small molecules for the modulation of protein and receptor signaling and subsequent gene expression.

For example, a hydrocarbon-stapled helical peptide called “BCL-2-interacting mediator of cell death (BIM) peptide” was able to overcome apoptotic resistance in hematologic cancers. A hydrocarbon stapled peptide modeled after the BIM BH3 helix broadly targeted BCL-2 family proteins with high affinity. This peptide was able to block inhibitory anti-apoptotic interactions thereby directly triggering proapoptotic activity inducing dose-responsive and BH3 sequence-specific cell death of hematologic cancer cells.

The therapeutic potential of the peptide was established by the selective activation of cell death in the aberrant lymphoid infiltrates of mice reconstituted with BIM-deficient bone marrow and in a human AML xenograft model. Therefore stapled peptides offer new ways to treat so called “undruggable” diseases.

What makes stapled peptides different?

Proteases, naturally present in the human body, can only recognize and digest peptides when they are unfolded. However, if the peptides are locked into certain folded shapes, they are protected from the attack of the proteases and will longer remain in the tissues where the targeted compounds reside.

How are stapled peptides made?

Key steps for the design of stapling peptides involves using a cross-linking chemistry that locks the peptides into α-helical shape that mimics the structure found at the interface of many protein-protein interactions. One prominent method is the hydrocarbon stapling approach.

What makes the peptide cell permeable?

A distance-matching bisaryl cross-linker can reinforce peptide helices containing two cysteines at the i.i+7 positions and confer cell permeability to the cross-linked peptides. Solid-phase peptide synthesis can be used for the synthesis of hydrogen-bond surrogate-derived artificial α-helices using a ring-closing metathesis reaction. Typically stapled peptides range in sizes from 12 to 35 amino acids in length. Short water-stable α-helices have been shown to maintain biological potency. In addition, shorter cyclic peptides can mimic the α-helical parts of a protein structure, have biological activity and are more stable than the parent proteins.