Stapled Peptides as Potential Therapeutics

Abstract

Stapled peptides are an important class of conformationally constrained, bioactive α‐helical peptides. They have been used extensively as chemical probes for the regulation of protein–protein interactions (PPIs), with one currently progressing through late‐stage clinical trials as a peptide drug candidate. Their ability to interact with shallow protein–protein interfaces, which have previously proven to be challenging to target with small molecules, has led to their rapid uptake by the chemical biology and drug discovery communities. Stapled peptides overcome some of the undesirable physicochemical properties that limit the use of peptides as therapeutics. They generally exhibit good binding affinity and specificity as they aim to accurately reproduce the α‐helix recognition motif from a PPI interface. They are protease resistant and in some instances have shown good cell permeability. The development of stapled peptides has thus resulted in a transformative shift by validating difficult PPIs as therapeutic targets and providing promising drug candidates. Key Concepts Stapled peptides are conformationally constrained α‐helical peptides. Stapling reduces the entropic penalty of folding to produce the bioactive conformation, thus giving an increase in binding affinity over an unfolded peptide. Through mimicking the interface these compounds have good binding affinity and specificity. Proteolytic stability is enhanced through the induction of secondary structure and the effective shielding of the peptide backbone from recognition by protease enzymes. Cell permeability can be enhanced by peptide stapling as the distribution of lipophilicity compared to the native peptide is altered. Key PPIs implicated in cancer, including p53‐MDM2/MDMX, Aurora‐A/TPX2 and the Bcl family, have been probed using stapled peptides.

Stapled ACE2 peptidomimetics designed to target the SARS‐CoV‐2 spike protein do not prevent virus internalization

“…[17,18] They have been shown in numerous biologically relevant examples (e.g., p53/MDM2, Bcl2 and Aurora-A/TPX2) to have excellent binding affinity, selectivity and also favorable DMPK properties. [19] Soluble ACE2 has been investigated as a potential therapeutic, acting as a competitive interceptor of SARS-CoV-2 and preventing viral binding to cells. [20] Recent studies have shown that human recombinant soluble ACE2 (hrsACE2) have shown promise for treating severe COVID-19.…”

μ‐Conotoxin KIIIA peptidomimetics that block human voltage‐gated sodium channels

“…We employed the hydrocarbon‐stapling (HCS) strategy developed by Verdine and co‐workers [ 32 ] as the unnatural amino acids required are commercially available. [ 33 ] The linear peptide 13 incorporating ( R )‐N‐Fmoc‐α‐(7‐octenyl) alanine at position i and ( S )‐N‐Fmoc‐α‐(4‐pentenyl)alanine at position i + 7 was prepared using standard Fmoc/ t Bu SPPS methods. Linear peptide 14 , incorporating two ( S )‐N‐Fmoc‐α‐(4‐pentenyl)alanine residues in the i and i + 4 positions (Scheme 2C) was also prepared to provide the shorter conformational constraint.…”

“…We employed the hydrocarbon-stapling (HCS) strategy developed by Verdine and co-workers [32] as the unnatural amino acids required are commercially available. [33] The Furthermore, as RCM of peptide 13 produced both the cis and trans isomers 3 and 4 and to investigate further the effect of the carbon-carbon double bond on the effectiveness of the hydrocarbon constraint, we also produced the reduced i,i + 7 staple 5. After RCM to produce peptides 3 and 4, the double bond was reduced on resin, using triisopropylbenzenesulfonyl hydrazide under basic conditions and elavated temperature to provide saturated stapled peptide 5 (Scheme 2B).…”

The Role of Apoptosis as a Double-Edge Sword in Cancer

“…In this regard, peptide-based inhibitors have been significant achievements in targeting and regulating intracellular protein-protein interaction. Stapled peptides are synthetic, bioactive α-helical peptides locked into their bioactive structure that have brought new hope to target drug discovery [135,136]. For instance, stabilized alpha-helix of Bcl-2 domains, SAHBs, is the peptide having the ability to penetrate leukaemia cells and trigger induction of apoptosis through its binding to the Bcl-xL which its function has been further confirmed though invivo mouse xenograft models of leukaemia [137].…”