Baumann Tobias, Nickling Jessica H, Bartholomae Maike, Buivydas Andrius, Kuipers Oscar P, Budisa Nediljko
Biocatalysis Group, Department of Chemistry, Technische Universität Berlin (Berlin Institute of Technology) Berlin, Germany.
Molecular Genetics Group, Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute, Rijksuniversiteit Groningen (University of Groningen) Groningen, Netherlands.
Front Microbiol. 2017 Feb 2;8:124. doi: 10.3389/fmicb.2017.00124. eCollection 2017.
The incorporation of non-canonical amino acids (ncAA) is an elegant way for the chemical diversification of recombinantly produced antimicrobial peptides (AMPs). Residue- and site-specific installation methods in several bacterial production hosts hold great promise for the generation of new-to-nature AMPs, and can contribute to tackle the ongoing emergence of antibiotic resistance in pathogens. Especially from a pharmacological point of view, desirable improvements span pH and protease resistance, solubility, oral availability and circulation half-life. Although the primary focus of this report is on ribosomally synthesized and post-translationally modified peptides (RiPPs), we have included selected cases of peptides produced by solid phase peptide synthesis to comparatively show the potential and impact of ncAA introduction. Generally speaking, the introduction of ncAAs in recombinant AMPs delivers novel levels of chemical diversification. Cotranslationally incorporated, they can take part in AMP biogenesis either through direction interaction with elements of the post-translational modification (PTM) machinery or as untargeted sites with unique physicochemical properties and chemical handles for further modification. Together with genetic libraries, genome mining and processing by PTM machineries, ncAAs present not a mere addition to this process, but a highly diverse pool of building blocks to significantly broaden the chemical space of this valuable class of molecules. This perspective summarizes new developments of ncAA containing peptides. Challenges to be resolved in order to reach large-scale pharmaceutical production of these promising compounds and prospects for future developments are discussed.
非标准氨基酸（ncAA）的掺入是一种巧妙的方法，可实现重组生产的抗菌肽（AMP）的化学多样化。几种细菌生产宿主中的残基特异性和位点特异性安装方法对于生成新型天然AMP具有巨大潜力，并有助于应对病原体中不断出现的抗生素耐药性问题。特别是从药理学角度来看，理想的改进包括pH和蛋白酶抗性、溶解度、口服可用性和循环半衰期。尽管本报告的主要重点是核糖体合成和翻译后修饰的肽（RiPPs），但我们纳入了通过固相肽合成产生的肽的选定案例，以比较展示引入ncAA的潜力和影响。一般来说，在重组AMP中引入ncAA可实现新的化学多样化水平。共翻译掺入时，它们可以通过与翻译后修饰（PTM）机制的元件直接相互作用，或作为具有独特物理化学性质和化学处理基团的非靶向位点参与AMP生物合成，以便进一步修饰。与基因文库、基因组挖掘和PTM机制处理一起，ncAA不仅仅是这个过程的补充，而是一个高度多样化的构建模块库，可显著拓宽这类有价值分子的化学空间。这篇综述总结了含ncAA肽的新进展。讨论了为实现这些有前景的化合物的大规模药物生产需要解决的挑战以及未来发展的前景。
