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Global analysis of peptide cyclization efficiency.

ABSTRACT: Cyclic peptides are of considerable interest in drug discovery and nanotechnology. However, macrocyclization of peptides and other compounds has often been perceived as synthetically challenging and the cyclization yields are affected by several factors including the ring size, peptide sequence, and the reaction conditions. Through the screening of combinatorial peptide libraries, we analyzed the cyclization efficiency of >2 million peptide sequences to determine the effect of ring size, peptide sequence, and solvent on the backbone (N-to-C) cyclization of peptides. Our results show that on-resin cyclization of medium- and large-sized rings (cyclohexapeptides and above) with PyBOP is essentially quantitative for ? 99.96% of the sequences, with small amounts of dimer formation observed for <4% of these sequences. Cyclization of small rings (cyclotetrapeptides and cyclopentapeptides) is considerably more difficult and accompanied by significant cyclic dimer formation. Peptides that are difficult to cyclize are generally rich in Lys(Boc) and Arg(Pbf) residues as well as sterically hindered residues [e.g., Thr(tBu)] at the N-terminus. The majority of these difficult sequences can be cyclized to completion by the addition of aqueous additives to the cyclization reaction.

SUBMITTER: Thakkar A

PROVIDER: S-EPMC3570731 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Global analysis of peptide cyclization efficiency.

Thakkar Amit A Trinh Thi Ba TB Pei Dehua D

ACS combinatorial science 20130107 2

Cyclic peptides are of considerable interest in drug discovery and nanotechnology. However, macrocyclization of peptides and other compounds has often been perceived as synthetically challenging and the cyclization yields are affected by several factors including the ring size, peptide sequence, and the reaction conditions. Through the screening of combinatorial peptide libraries, we analyzed the cyclization efficiency of >2 million peptide sequences to determine the effect of ring size, peptide ...[more]

PMID: 23265659

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Project description:Peptide cyclization is a strategy used to improve stability and activity of peptides. The most commonly used cyclization method is disulfide bridge formation of cysteine-containing peptides, as is typically found in nature. Over the years, an increasing number of alternative chemistries for peptide cyclization with improved efficiency, kinetics, orthogonality, and stability have been reported. However, there has been less appreciation for the opportunity to fine-tune peptide activity via the diverse chemical entities introduced at the site of linkage by different cyclization strategies. Here, we demonstrate how cyclization optimization of an M2 "anti-inflammatory" macrophage-binding peptide (M2pep) resulted in a significant increase in binding affinity of the optimized analog to M2 macrophages while maintaining binding selectivity compared to M1 "pro-inflammatory" macrophages. In this study, we report synthesis and evaluation of four cyclic M2pep(RY) analogs with diverse cyclization strategies: (1) Asp-[amide]-Lys, (2) azido-Lys-[triazole(copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC))]-propargyl-Gly, (3) Cys-[decafluorobiphenyl (DFBP)]-Cys, and (4) Cys-[decafluorobiphenyl sulfone (DFS)]-Cys, whereby the chemical entity or linker at the linkage site is shown in the square bracket and is between the residues involved in cyclization. These peptides are compared to a disulfide-cyclized M2pep(RY) that we previously reported as a serum-stable, affinity-enhanced analog to the original linear M2pep. DFBP-cyclized M2pep(RY) exhibits the highest binding activity to M2 macrophages with apparent dissociation constant (KD) about 2.03 μM compared to 36.3 μM for the original disulfide-cyclized M2pep(RY) and 220 μM for the original linear peptide. DFS-cyclized M2pep(RY) also binds more strongly than the original cyclized analog, whereas amide- and triazole-cyclized M2pep(RY) analogs bind less strongly. We verified that DFBP alone has negligible binding to M2 macrophages and the incorporation of diphenylalanine to the original sequence improves binding activity at the expense of solubility and increased toxicity. In conclusion, we report development of cyclic M2pep(RY) analogs with diverse cyclization strategies leading to the discovery of DFBP-cyclized M2pep(RY) with enhanced M2 macrophage-binding activity.

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Global analysis of peptide cyclization efficiency.

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Global analysis of peptide cyclization efficiency.

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