Fmoc-Based Synthesis of Disulfide-Rich
Cyclic Peptides
Olivier Cheneval
Christina I. Schroeder
Thomas Durek
Phillip Walsh
Yen-Hua Huang
Spiros Liras
David
A. Price
David J. Craik
10.1021/jo500699m.s001
https://acs.figshare.com/articles/journal_contribution/Fmoc_Based_Synthesis_of_Disulfide_Rich_Cyclic_Peptides/2280885
Disulfide-rich cyclic
peptides have exciting potential as leads
or frameworks in drug discovery; however, their use is faced with
some synthetic challenges, mainly associated with construction of
the circular backbone and formation of the correct disulfides. Here
we describe a simple and efficient Fmoc solid-phase peptide synthesis
(SPPS)-based method for synthesizing disulfide-rich cyclic peptides.
This approach involves SPPS on 2-chlorotrityl resin, cyclization of
the partially protected peptide in solution, cleavage of the side-chain
protecting groups, and oxidization of cysteines to yield the desired
product. We illustrate this method with the synthesis of peptides
from three different classes of cyclic cystine knot motif-containing
cyclotides: MoĢbius (M), trypsin inhibitor (T), and bracelet
(B). We show that the method is broadly applicable to peptide engineering,
illustrated by the synthesis of two mutants and three grafted analogues
of kalata B1. The method reduces the use of highly caustic and toxic
reagents and is better suited for high-throughput synthesis than previously
reported methods for producing disulfide-rich cyclic peptides, thus
offering great potential to facilitate pharmaceutical optimization
of these scaffolds.
2014-06-20 00:00:00
peptide engineering
SPPS
kalata B 1.
drug discovery
method
synthesis
cyclic