Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics

Abstract

Peptide and protein aberrant lipidation patterns are often involved in many diseases including cancer and neurological disorders. Peptide lipidation is also a promising strategy to improve pharmacokinetic and pharmacodynamic profiles of peptide-based drugs. Self-adjuvanting peptide-based vaccines commonly utilise the powerful TLR2 agonist PamCys lipid to stimulate adjuvant activity. The chemical synthesis of lipidated peptides can be challenging hence efficient, flexible and straightforward synthetic routes to access homogeneous lipid-tagged peptides are in high demand. A new technique coined Cysteine Lipidation on a Peptide or Amino acid (CLipPA) uses a 'thiol-ene' reaction between a cysteine and a vinyl ester and offers great promise due to its simplicity, functional group compatibility and selectivity. Herein a brief review of various synthetic strategies to access lipidated peptides, focusing on synthetic methods to incorporate a PamCys motif into peptides, is provided.

Design of novel lipidated peptidomimetic conjugates for targeting EGFR heterodimerization in HER2 + cancer

“…Lipidation also leads to changes in the peptide secondary structures through hydrophobic interactions between the fatty acid chain and peptide backbone or side chain 24 without affecting specificity and binding affinities of peptides. Moreover, lipidation reduces peptide renal clearance and elevates plasma stability 25, 26 .…”

Peptides with Dual Antimicrobial–Anticancer Activity: Strategies to Overcome Peptide Limitations and Rational Design of Anticancer Peptides

“…Another conjugation of peptides is with lipids, which is also known as lipidation. It produces amphiphilic peptides with increased bioavailability, improving the half-life, receptor selectivity, potency, and membrane penetration [ 24 ]. Daptomycin is one of these lipopeptides, which is produced from natural lipidation and is widely used to treat diseases caused by Gram-positive bacteria.…”

“…Another example of natural lipidation is surfactin, which exhibits antimicrobial, antiviral, and antitumor activities [ 22 , 25 ]. Some of the peptides on the market that have gone through synthetic lipidation are liraglutide (Victoza ® ) and insulin detemir (Levemir ® ) [ 24 ].…”

Applications of Thiol-Ene Chemistry for Peptide Science

“…Approaches to chemical synthesis of lipopeptides include synthesis of lipid containing amino acids or modification of peptide chains to attach a lipid moiety, both of which have been achieved through application of thiol-ene chemistry. Modification of peptide chains via thiol-ene chemistry has been widely studied in the context of the CLipPA methodology developed by the Brimble group, involving use of fatty acid vinyl esters for attachment at Cys residues (Kowalczyk et al, 2017 ; Hermant et al, 2020 ).…”