Versatile convergent synthesis of a three peptide loop containing protein mimic of whooping cough pertactin by successive Cu(I)‐catalyzed azide alkyne cycloaddition on an orthogonal alkyne functionalized TAC‐scaffold

Abstract

Synthetic mimics of discontinuous epitopes may have a wide range of potential applications, including synthetic vaccines and inhibition of protein-protein interactions. However, synthetic access to these relatively complex peptide molecular constructs is limited. This paper describes a versatile convergent strategy for the construction of protein mimics presenting three different cyclic peptides. Using an orthogonal alkyne protection strategy, peptide loops were introduced successively onto a triazacyclophane scaffold via Cu(I)-catalyzed azide alkyne cycloaddition. This method provides rapid access to protein mimics requiring different peptide segments for their interaction and activity.

Chemical biology tools for probing transcytosis at the blood–brain barrier

“…As demonstrated here and elsewhere, CuAAC mediated convergence provided rapid access to versatile bioconjugates that was reproducible. 19 Detailed characterisation data and yields for all conjugates are reported in Table S2. †…”

Current and future prophylactic vaccines for hepatitis C virus

“…The peptide structure could be changed chemically, for example, by cyclization or possibly linked to a chemical or protein scaffold. 128,129 Such changes of the natural structure could improve stability and antigenicity: a key issue with protein vaccination methods. A scaffold also offers the possibility of presenting multiple peptides in the correct orientation to mimic a discontinuous epitope in the native E2 structure.…”

The Development of a Versatile Trifunctional Scaffold for Biological Applications

“…Recently, during the preparation of our manuscript, the same group published a solid‐phase synthesis of triazacyclophane scaffolds derivatized with three arms, each bearing unprotected or orthogonally protected (triethylsilyl, TES and triisopropylsilyl, TIPS) alkyne moieties. After cleavage from the resin, three different cyclic peptides were introduced to the scaffold arms through Huisgen 1,3‐dipolar cycloaddition to yield new protein mimics 9b. Interesting, tripodal scaffold molecules functionalized with amino acids by solid‐phase synthesis were also reported by Van der Plas et al10 and by Guarise et al11…”