Stapled Peptides Inhibitors: A New Window for Target Drug Discovery

Abstract

Protein-protein interaction (PPI) is a hot topic in clinical research as protein networking has a major impact in human disease. Such PPIs are potential drugs targets, leading to the need to inhibit/block specific PPIs. While small molecule inhibitors have had some success and reached clinical trials, they have generally failed to address the flat and large nature of PPI surfaces. As a result, larger biologics were developed for PPI surfaces and they have successfully targeted PPIs located outside the cell. However, biologics have low bioavailability and cannot reach intracellular targets. A novel class -hydrocarbon-stapled α-helical peptides that are synthetic mini-proteins locked into their bioactive structure through site-specific introduction of a chemical linker- has shown promise. Stapled peptides show an ability to inhibit intracellular PPIs that previously have been intractable with traditional small molecule or biologics, suggesting that they offer a novel therapeutic modality. In this review, we highlight what stapling adds to natural-mimicking peptides, describe the revolution of synthetic chemistry techniques and how current drug discovery approaches have been adapted to stabilize active peptide conformations, including ring-closing metathesis (RCM), lactamisation, cycloadditions and reversible reactions. We provide an overview on the available stapled peptide high-resolution structures in the protein data bank, with four selected structures discussed in details due to remarkable interactions of their staple with the target surface. We believe that stapled peptides are promising drug candidates and open the doors for peptide therapeutics to reach currently “undruggable” space.

Macrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled α-helical peptide modality

“…The stitched peptide displayed the highest helicity (52%) while the double stapled peptide remained unchanged at 20%, similar to that adopted by the linear peptide. Nevertheless, both these peptides displayed increased binding to Mdm2, suggesting that the binding 16 mechanism of these peptides are different from each other. However only the stitched peptide displayed increased cellular activity, probably resulting from increased cell permeability; the double stapled peptide appears unable to cross the cell membrane.…”

“…Thirdly, macrocyclization may enhance cell permeability, such as through increased stability of intramolecular hydrogen bonding to reduce the desolvation penalty otherwise incurred in the transport of peptides across an apolar cell membrane. Amongst the several cyclization techniques described, stapling via olefin metathesis using a non-proteogenic amino acid such as alpha-methyl alkenyl side chains has proven to be very effective [13][14][15][16][17][18], particularly when the desired secondary structure of the peptide macrocycle is helical. Stapling requires incorporation of the appropriate unnatural amino acid precursors to be placed at appropriate locations along the peptide sequence such that they do not interfere with the binding face of the helix.…”

Visualising the Experimentally Uncharted Territories of Membrane Protein Structures inside Protein Data Bank

“…In original PDB-format data, the experimentally determined atomic coordinates are presented in the ATOM records. Chances are that they do not exactly match the sequence (consisting of nucleic and/or amino acid residues) of the experimental sample per se, be it protein, DNA, RNA or their complexes with drugs and/or other small molecules [35][36][37]. In fact, this misalignment arises from the uncharted territories (i.e., missing residues) of MP experimental structures deposited in PDB.…”

A review on anti‐tuberculosis peptides: Impact of peptide structure on anti‐tuberculosis activity

“…[200][201][202] On the other hand, switching to other forms of cyclic bonds such as lactamisation, olefin metathesis, ruthenium-catalysed ring closure metathesis, Cu(I)-catalysed azide-alkyne cycloaddition, and thioether formation would also be beneficial for the therapeutic use of these peptides. [203][204][205][206][207][208][209]…”