Global analysis of peptide cyclization efficiency.
Global analysis of peptide cyclization efficiency.
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DOI：
10.1021/co300136j
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发表时间：
2013-02-11
影响因子：
--
通讯作者：
Pei, Dehua
中科院分区：
文献类型：
--
作者：
Thakkar, Amit;Thi Ba Trinh;Pei, Dehua
关键词：
环肽在药物发现和纳米技术中具有相当大的兴趣。然而，肽和其他化合物的大环化通常被认为是合成上具有挑战性的，并且环化产率受到包括环大小、肽序列和反应条件在内的若干因素的影响。通过筛选组合肽文库，我们分析了> 200万个肽序列的环化效率，以确定环大小、肽序列和溶剂对肽的骨架（N-to-C）环化的影响。我们的研究结果表明，对于≥99.96%的序列，使用PyBOP对中型和大型环（环己肽及以上）进行树脂环化基本上是定量的，对于<4%的序列观察到少量二聚体形成。小环（环四肽和环五肽）的环化相当困难，并且伴随着显著的环状二聚体形成。难以环化的肽通常富含Lys（Boc）和Arg（Pbf）残基以及空间位阻残基[例如，Thr（tBu）]。这些困难序列中的大多数可以通过向环化反应中加入水性添加剂而环化完成。
Cyclic peptides are of considerable interests 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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影响因子：
16.6
作者：
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作者：
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