Traceless native chemical ligation of lipid-modified peptide surfactants by mixed micelle formation

Abstract

Biology utilizes multiple strategies, including sequestration in lipid vesicles, to raise the rate and specificity of chemical reactions through increases in effective molarity of reactants. We show that micelle-assisted reaction can facilitate native chemical ligations (NCLs) between a peptide-thioesterin which the thioester leaving group contains a lipid-like alkyl chainand a Cys-peptide modified by a lipid-like moiety. Hydrophobic lipid modification of each peptide segment promotes the formation of mixed micelles, bringing the reacting peptides into close proximity and increasing the reaction rate. The approach enables the rapid synthesis of polypeptides using low concentrations of reactants without the need for thiol catalysts. After NCL, the lipid moiety is removed to yield an unmodified ligation product. This micelle-based methodology facilitates the generation of natural peptides, like Magainin 2, and the derivatization of the protein Ubiquitin. Formation of mixed micelles from lipid-modified reactants shows promise for accelerating chemical reactions in a traceless manner.

Tuning the Activity of Anoplin by Dendrimerization of Lysine and Lipidation of the N-Terminal

“…In conclusion, in the development of AMPs, excessive chemical modifications may not be necessary for some peptides. In contrast, simple modifications may lead to unexpected and satisfactory results. − The direct lipidation of a single anoplin is better than the lipidation after dendrimerization for antibacterial performance and cell selectivity. Dendrimerization increases the hydrophobicity, cationic nature, α-helicity, and multi-valency of these compounds, thereby increasing the antibacterial activity.…”

Methods for Studying Site-Specific O-GlcNAc Modifications: Successes, Limitations, and Important Future Goals

“…Additionally, certain protein fragments can suffer from poor expression yields and unpredictable physical properties that make them difficult to purify in sufficient quantities. Therefore, methods that increase the rate of protein ligation, such as a lipid-facilitated protocol published by the Devaraj lab, 92 are still incredibly important for the field and should be explored. Additionally, robust and gentle ligation reactions that occur at noncysteine or -alanine junctions would greatly expand the potential viable synthetic strategies to any given protein target.…”

Production of constrained L-cyclo-tetrapeptides by epimerization-resistant direct aminolysis

“…Despite their pharmacological promise, the study of cyclic tetrapeptides and the scope of related research are hampered by limited synthetic capabilities 25 , 26 . Nonetheless, cyclic tetrapeptides, regarded as “privilege molecules,” 27 , 28 possess constrained motifs, adhere to Lipinski 29 rules, and exhibit promise for improved interactions with biomolecules 30 – 32 and blood–brain barrier penetration 33 .

Fig.

…”