Cyclic Peptoid-Peptide Hybrids as Versatile Molecular Transporters

Abstract

Addressing intracellular targets is a challenging task that requires potent molecular transporters capable to deliver various cargos. Herein, we report the synthesis of hydrophobic macrocycles composed of both amino acids and peptoid monomers. The cyclic tetramers and hexamers were assembled in a modular approach using solid as well as solution phase techniques. To monitor their intracellular localization, the macrocycles were attached to the fluorophore Rhodamine B. Most molecular transporters were efficiently internalized by HeLa cells and revealed a specific accumulation in mitochondria without the need for cationic charges. The data will serve as a starting point for the design of further cyclic peptoid-peptide hybrids presenting a new class of highly efficient, versatile molecular transporters.

Advance in Hybrid Peptides Synthesis

“…This method also provides the possibility for expanding applications and becomes a classic method for peptide/peptoid hybrid synthesis. [52,[93][94][95] In addition, Ugi four-component reaction (Ugi-4CR) could be used to synthesize peptoid with specific amide substitution. [96] In a typical Ugi-4CR, a stoichiometric mixture of aldehyde, amine, isonitrile, and carboxylic acid produces corresponding dimeric peptide/peptoid.…”

“…This method also provides the possibility for expanding applications and becomes a classic method for peptide/peptoid hybrid synthesis. [ 52,93–95 ]…”

Structure – Bioactivity Relationship in Cyclic Peptoids: An Overview

“…Rhodamine was chosen by Bräse and collaborators [82] as a fluorescent probe installed on cell penetrating cyclic tetra-and hexameric peptide/peptoid hybrids. Figure 17 According to the authors, generation of a hybrid structure with retention of amino acid monomers is fundamental to increase biological activity.…”

“…Rhodamine was chosen by Bräse and collaborators [82] as a fluorescent probe installed on cell penetrating cyclic tetra‐ and hexameric peptide / peptoid hybrids. Figure 17 displays the most active derivative, obtained by mixing monomeric/sub‐monomeric protocols.…”

Using Enhanced Sampling Simulations to Study the Conformational Space of Chiral Aromatic Peptoid Monomers

“…For this reason, peptoids are also resistant to protease action as they do not fit into protease-binding pockets, which are usually tuned specifically to peptides. , The folding properties and the secondary structure expressed by a peptoid polymer can be controlled by altering the conditions during manufacturing. ,,, Experiments have also shown that peptoids have enhanced cellular uptake properties while maintaining reduced immune responses, unlike most peptidomimetics. , All of these features make peptoid attractive candidates for investigation using both experimental and computational means. Potential applications of peptoids as curative and preventative medicine and intracellular drug delivery vehicles rely heavily on these properties. − Peptoids are well suited for a wide variety of material discovery applications such as antimicrobial and antifungal coatings, ,− energy transfer or storage systems, , and mimics of biologically occurring materials . These uses, along with the ease of synthesizing them using the submonomer synthesis method, make them one of the most promising biomolecules currently being investigated.…”