Stapled Peptides—A Useful Improvement for Peptide-Based Drugs

Abstract

Peptide-based drugs, despite being relegated as niche pharmaceuticals for years, are now capturing more and more attention from the scientific community. The main problem for these kinds of pharmacological compounds was the low degree of cellular uptake, which relegates the application of peptide-drugs to extracellular targets. In recent years, many new techniques have been developed in order to bypass the intrinsic problem of this kind of pharmaceuticals. One of these features is the use of stapled peptides. Stapled peptides consist of peptide chains that bring an external brace that force the peptide structure into an α-helical one. The cross-link is obtained by the linkage of the side chains of opportune-modified amino acids posed at the right distance inside the peptide chain. In this account, we report the main stapling methodologies currently employed or under development and the synthetic pathways involved in the amino acid modifications. Moreover, we report the results of two comparative studies upon different kinds of stapled-peptides, evaluating the properties given from each typology of staple to the target peptide and discussing the best choices for the use of this feature in peptide-drug synthesis.

Variable‐Length Ester‐Based Staples for α‐Helical Peptides by Using A Double Thiol‐ene Reaction

“…PPIs are often mediated through α‐helical peptide motifs and can be effectively blocked by peptide therapeutics, which cover a greater surface area and mimic key amino acid interactions. The installation of a backbone constraint on an α‐helical peptide, now commonly referred to as peptide stapling, can improve the therapeutic properties of these bioactive helical peptides, including structural stability, proteolytic stability and cell permeability . By overcoming the typical shortcomings of therapeutic peptides, stapled α‐helical peptides have become an exciting new modality for generating clinical candidates as well as chemical tools for investigating signalling pathways in cells .…”

Design and Synthesis of Helical N-Terminal l-Prolyl Oligopeptides Possessing Hydrocarbon Stapling

“…In 2000, Verdine’s group reported all-hydrocarbon stapling using α-olefin-tethered alanine at i , i +4 as well as at i , i +7 positions, and the introduction of these staples highly induced α-helicities as well as the metabolic stabilities of the peptides [ 6 ]. Nowadays, the all-hydrocarbon staplings at the i , i +4 and i , i +7 positions are widely used in the medicinal chemistry of peptides [ 7 , 8 , 9 ].…”

Design and Creation of Functional Membrane-Interacting Peptides

“…Stapled peptides constitute a popular type of structurally restricted peptides; their helical structures are stabilized by cross linking the side chains of two amino acids separated by one or two turns in helices. 15,16 Secondary structures (e.g., α helices, β sheets, and β turns) are formed and maintained in proteins by hydrogen bonding, electrostatic interactions, and hydrophobic interactions with other peptide segments. 17 Therefore, isolated peptide segments with helix forming propensity do not generally form the expected structures because of the absence of other peptide segments.…”