General and Facile Route to Isomerically Pure Tricyclic Peptides Based on Templated Tandem CLIPS/CuAAC Cyclizations

Abstract

We report aone-pot ligation/cyclization technology for the rapid and clean conversion of linear peptides into tricyclic peptides that is based on using tetravalent scaffolds containing two benzyl bromide and two alkyne moieties.These react via CLIPS/CuAACreactions with cysteines and azides in the peptide.Flexibility in the scaffolds is key to the formation of isomerically pure products as the flexible scaffolds T4 1 and T4 2 mostly promote the formation of single isomeric tricycles while the rigid scaffolds T4 3 and T4 4 do not yield clean products. There seems to be no limitation to the number and types of amino acids present as 18 canonical amino acids were successfully implemented. We also observed that azides at the peptide termini and cysteine residues in the center gave better results than compounds with the functional groups placed the other wayr ound.Cyclic peptides have emerged as ap romising class of drug compounds [1][2][3][4] showing aw ide therapeutic window that ranges from antifertility [5] to anticancer [6][7][8] and antiviral [9][10][11] applications.A st he number of cyclic peptides entering clinical trials has drastically increased over the last years, [6] the search for novel synthetic routes to multicyclic peptides has received significant interest. [12][13][14][15][16][17][18][19][20][21][22][23] In 2005, our group introduced "CLIPS technology" (chemical linkage of peptides onto scaffolds), which involves the tandem ligation/cyclization of tris(cysteine)-containing linear peptides with a,a',a''-tribromomesitylene (T3)t og ive the corresponding bicyclic peptides. [12] Heinis and co-workers applied this technology in phage display libraries,r eaching diversity levels as high as 10 9 -10 13 different bicycles. [13] Biological evaluation against various proteins [13][14][15][16] identified potent bicyclic peptides with K i values in the nanomolar range.I ns ome cases,t he best inhibitors displayed only (sub)micromolar activities, [24] suggesting that higher-order structures,such as tricycles,may be needed to reach improved activity levels.V ancomycin, alast-resort antibiotic consisting of aglycopeptide wrapped around an aromatic core,provides an illustrative example of such ac omplex architecture (Figure 1). [25] Currently,c omplex syntheses impede the large-scale production of vancomycin-like drugs,and complicate structural diversification processes aimed at optimizing their biological activities. [26] Examples of synthetic tricyclic peptides have been reported as the groups of both Ruchala [17] and Wu [18] used either a T h -o raD 2h -symmetric scaffold to assemble linear peptides into tricycles,w hile Suga, [19] Nuijens, [20] and our group [21] used various types of backbone cyclization in combination with T3 CLIPS.T hese and other examples emphasize the interest in multicyclic peptides although the formation of multiple isomers,laborious reaction procedures, as well as difficulties in generating structural diversity remain delicate issues.CLIPS reactions of tetrakis(cysteine)-containing pept...

New Method toward a Robust Covalently Attached Cross-Linked Nanofiltration Membrane

“…The resulting products were made via the reaction of cysteine-based peptides as thiol substituted with benzylic bromides under mild basic conditions (pH ∼ 8). 15 The method was expanded to the preparation of polymers by Monnereau et al in 2015. 16 Hyper-cross-linked thioether-based porous polymers were formed under similar conditions.…”

Bioinformatics leading to conveniently accessible, helix enforcing, bicyclic ASX motif mimics (BAMMs)

“…Frequent occurrence of hydrophobic triangles in protein ASX motifs, and their unexpectedly high impact on model peptides, led us to hypothesize replacement of the hydrophobic N', N3, and N4 side chains by a single hydrophobic fragment covalently linked to all three residues would rigidly stabilize the helical N-cap. We saw a way to achieve this using CLIPs (Chemical LInkage of Peptides onto Scaffolds) chemistry [28][29][30][31] . Chemoselective CLIPS reactions of electrophiles with Cys and Cys-derivative thiols is emerging as the peptidic equivalent of click reactions 32 in organic methodology.…”