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Global Analysis of Peptide Cyclization Efficiency

期刊

ACS COMBINATORIAL SCIENCE
卷 15, 期 2, 页码 120-129

出版社

AMER CHEMICAL SOC
DOI: 10.1021/co300136j

关键词

cyclic peptides; macrocyclization; combinatorial chemistry; one-bead-two-compound library; partial Edman degradation; peptide sequencing

资金

  1. National Institutes of Health [GM062820, T32 GM08512]

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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.

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