Thus, improved compositions and strategies for making stapled peptides are highly desirable. Generally speaking, the above-described linkers are hydrophobic, which often causes solubility problems. Owing to the increasing interest in stapled peptides and other conformationally restricted structures, many efforts have been made to develop alternative practical and general preparative methods for their generation. These syntheses are expensive and laborious. Other methods involve ring-closing metathesis biaryl linkage of functionalized synthetic amino acids involving borylated phenylalanine derivatives or “click chemistry”, whereby cycloaddition between an azide and a terminal or internal alkyne yields a 1,2,3-Triazole ( FIG. The main strategies involve the use of cysteine side chains for forming disulfide bridges and thioether formation ( FIGS. There are various strategies for generating stapled peptides. For example, KD lactam-type peptides have been used as HIV and RSV PPI inhibitors, hydrocarbon-type peptides have been developed to promote Bcl2 apoptosis and inhibit HIV-1 capsid assembly or NOTCH transcription, and triazole-type peptides have been applied to PTH and β-catenin/Bcl9. 5A-5C and 5E-5G).Įach of these linkers has shown successful applications to some extent. To enhance the α-helix structural stability of these short synthetic peptides in water, various covalent sidechain-to-sidechain linking strategies have been developed to stabilize the α-helical structure, including KD lactam linkers, hydrocarbon linkers, “click” triazole linkers, m-xylene thioether linkers, perfluorobenzyl thioether linkers, and alkyl thioether linkers ( FIGS.
PPIs involving an oft-occurring protein α-helix of 1-4 helical turns (4-15 amino acids) are promising targets, because one can design and prepare synthetic α-helix peptide ligands as the receptor antagonist. Protein-protein interactions (PPIs) are involved in many biological processes, hence, the discovery of molecules that perturb PPIs has led to some attractive approaches in drug discovery. Stapled peptides exhibit higher specificity and affinity than small molecules, targeting intracellular control points that cannot be modulated by current therapeutics. Small molecules are also cell permeable, but they are more limited in the types of targets they can bind. A staple stabilizes a peptide in a configuration that matches the binding site of the protein target, it protects the peptide against proteolytic action, and it makes the peptide membrane permeable (Sun et al., Biophys. Stapling of a peptide using a hydrocarbon cross-linker created from an olefin metathesis reaction has been shown to help maintain a peptide's native conformation, particularly under physiological conditions (U.S. “Peptide stapling” is a term coined for a synthetic methodology used to covalently join two olefin-containing side chains present in a peptide chain using an olefin metathesis reaction (J. However, α-helical peptides have a propensity for unraveling and forming random coils, which are, in most cases, biologically less active, or even inactive, and are highly susceptible to proteolytic degradation. The α-helix is one of the major structural components of proteins and is often found at the interface of protein contacts, participating in a wide variety of intermolecular biological recognition events.
One effective strategy of stabilizing peptides involves locking them into specific, protease-resistant shapes. Their use for modulating intracellular processes is hampered by their inability to enter cells, their instability, and their susceptibility to proteases. Peptides are valuable and effective drugs for targeting extracellular receptors. The disclosed invention is generally in the field of functionalized peptides and specifically in the area of stapled helical peptides. 1, 2015, is hereby incorporated herein by reference in its entirety.
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