Efficient parallel synthesis of macrocyclic peptidomimetics

Marsault, Éric; Hoveyda, Hamid R.; Gagnon, René; Peterson, Mark L.; Vézina, Martin; Saint-Louis, Carl Jacky; Landry, Annick; Pinault, Jean François; Ouellet, Luc; Beauchemin, Sophie; Beaubien, Sylvie; Mathieu, Axel; Benakli, Kamel; Wang, Zhigang; Brassard, Martin; Lonergan, David; Bilodeau, François; Ramaseshan, Mahesh; Fortin, Nadia; Lan, Ruoxi; Li, Shigui; Galaud, Fabrice; Plourde, V.; Champagne, Manon; Doucet, Annie; Bhérer, Patrick; Gauthier, Maude; Olsen, Gilles; Villeneuve, G.; Bhat, Shridhar; Foucher, Laurence; Fortin, Daniel; Peng, Xiaowen; Bernard, Sylvain; Drouin, Alexandre; Déziel, Robert; Berthiaume, Gilles; Dory, Yves L.; Fraser, Graeme L.; Deslongchamps, Pierre

doi:10.1016/j.bmcl.2008.06.085

Cited by 36 publications

(33 citation statements)

References 35 publications

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“…A versatile parallel synthesis platform aimed at macrocycles (macrocyclic template chemistry, MATCH) has been developed 108 . In this method, macrocycles are made using a non-peptidic tether that forces a peptide sequence into a head-to-tail cyclization.…”

Section: Libraries Of Peptide Macrocyclesmentioning

confidence: 99%

Contemporary strategies for peptide macrocyclization

2011

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Peptide macrocycles have found applications that range from drug discovery to nanomaterials. These ring-shaped molecules have shown remarkable capacity for functional fine-tuning. Such capacity is enabled by the possibility of adjusting the peptide conformation using the techniques of chemical synthesis. Cyclic peptides have been difficult, and often impossible, to prepare using traditional synthetic methods. For macrocyclization to occur, the activated peptide must adopt an entropically disfavoured pre-cyclization conformation before forming the desired product. Here, we review recent solutions to some of the major challenges in this important area of contemporary synthesis.

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Section: Libraries Of Peptide Macrocyclesmentioning

confidence: 99%

Contemporary strategies for peptide macrocyclization

2011

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“…Degrado and coworkers (46), Boger and Myers (47), and others have shown the utility of such template-constrained cyclic peptides (48,49), and how polarity and geometry of the template can influence the shape and function of the peptide domain (50). Our laboratory has also explored templates for forming macrocyclic peptides (51)(52)(53).…”

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confidence: 94%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide-protein interactions are important mediators of cellularsignaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. S ynthetic peptides and peptidomimetics play wide-ranging roles in pharmacology and drug discovery. Interest in these substances continues to grow, particularly as medicinal chemistry pushes further into control of cellular-signaling events mediated by protein-protein interactions (PPIs) (1-3). The subset of socalled "druggable" PPIs includes those mediated by consensus peptides, where binding determinants are localized within defined motifs (4-8). Experimental data as well as computational/ bioinformatic efforts (9-11) to identify "short linear motifs" within signaling proteins suggest that the number of druggable PPIs has been underestimated (12, 13). Considerable opportunity exists for new chemistry in this area (14). Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15-19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).Ring-forming reactions are prominent among alterations found to improve the stability and performance of peptides (24-27). They find broad utility in synthesis and, increasingly, in combination with phage, ribosome, and mRNA display technologies (28-32). Relative to their acyclic counterparts, cyclic peptides have more defined conformations and are less prone to aggregate (33). Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34-36). Internal disulfide bonding is also used (37, 38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40-42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig. 1A) (43, 44). Careful attention must be paid to...

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“…Validated outcome measurements including the visual analog scale (VAS) at rest and with activity, 15 the American Shoulder and Elbow Society score and the short form-36 (SF36) scores were obtained preoperatively and at long-term follow-up. 16 Clinical parameters including active and passive forward elevation, external rotation, and internal rotation were collected preoperatively and postoperatively. Twenty-two patients with minimum one-year follow up were available for evaluation.…”

Section: Methodsmentioning

confidence: 99%

The global percutaneous shuttling technique tip for arthroscopic rotator cuff repair

2014

Orthop Rev

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Most arthroscopic rotator cuff repairs utilize suture passing devices placed through arthroscopic cannulas. These devices are limited by the size of the passing device where the suture is passed through the tendon. An alternative technique has been used in the senior author’s practice for the past ten years, where sutures are placed through the rotator cuff tendon using percutaneous passing devices. This technique, dubbed the global percutaneous shuttling technique of rotator cuff repair, affords the placement of sutures from nearly any angle and location in the shoulder, and has the potential advantage of larger suture bites through the tendon edge. These advantages may increase the area of tendon available to compress to the rotator cuff footprint and improve tendon healing and outcomes. The aim of this study is to describe the global percutaneous shuttling (GPS) technique and report our results using this method. The GPS technique can be used for any full thickness rotator cuff tear and is particularly useful for massive cuff tears with poor tissue quality. We recently followed up 22 patients with an average follow up of 32 months to validate its usefulness. American Shoulder and Elbow Surgeons scores improved significantly from 37 preoperatively to 90 postoperatively (P<0.0001). This data supports the use of the GPS technique for arthroscopic rotator cuff repair. Further biomechanical studies are currently being performed to assess the improvements in tendon footprint area with this technique.

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Efficient parallel synthesis of macrocyclic peptidomimetics

Cited by 36 publications

References 35 publications

Contemporary strategies for peptide macrocyclization

Contemporary strategies for peptide macrocyclization

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

The global percutaneous shuttling technique tip for arthroscopic rotator cuff repair

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