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Template-mediated N-to-C-terminal assembly of peptide chains and cyclic peptides on programmable heterodimeric coiled-coil scaffolds

模板介导的肽链和环肽在可编程异二聚卷曲螺旋支架上的 N 端到 C 端组装

基本信息

批准号：
273442375
负责人：
Professorin Dr. Franziska Thomas
金额：
--
依托单位：
Organisch-Chemisches Institut
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/273442375?language=en
关键词：
Template mediated terminal assembly peptide

项目摘要

Most biochemical processes in organisms are mediated by proteins such as enzymes and multi-protein complexes. None of the state-of-the-art catalysts can compete with the biological synthesis machineries in terms of efficiency and selectivity. Protein function is directed by the three dimensional structure which is based on the underlying amino-acid sequence. Exploring sequence-to-structure-to-function relationships is not only fundamental to our understanding of the function of known proteins but also the basis for the design of new functional proteins and peptides.Simple sequence-to-structure-relationships are understood for the beta-strand, the alpha-helical coiled coil, the collagen triple helix and in part for the zinc-finger motif and the WW-domain. However, these few folding motifs cover properties such as controlled oligomerisation and association as well as protein- and DNA-recognition, which would allow the design of simple functional systems. This research project aims to use the de novo designed parallel heterodimeric coiled-coil motif as a template in the synthesis of peptide chains and cyclic peptides. The synthesis strategy is based on the association of coil strands, which are linked to the amino acid to be transferred and to the growing peptide chain via a thioester bond. Based on the chemistry of the native chemical ligation, the peptide chain is elongated from the N-to the C-terminus. The thioester linkage allows subsequent head-to-tail cyclization, which is also intended to be mediated by coiled-coil interaction. It is planned to develop a solid-phase and a solution-phase synthesis approach. For the solid-phase synthesis, control of the individual reaction steps is achieved by tuning the reaction-buffer conditions. However, to control the coiled-coil-mediated peptide synthesis in solution, a coiled-coil code using orthogonally interacting coiled coils will be developed. Both synthesis strategies will be applied in the design and assembly of cyclic peptide libraries.The project is based in the research field of synthetic biology which aims to use simple building blocks to mimic complex biological systems.

生物体中的大多数生化过程都是由酶和多蛋白复合体等蛋白质介导的。在效率和选择性方面，没有一种最先进的催化剂可以与生物合成机器相媲美。蛋白质的功能是由以氨基酸序列为基础的三维结构来指导的。探索序列-结构-功能的关系不仅是我们理解已知蛋白质功能的基础，也是设计新的功能蛋白质和多肽的基础。简单的序列-结构关系被理解为β-链、α-螺旋螺旋、胶原三螺旋以及部分锌指基序和WW-结构域。然而，这几个折叠基序涵盖了受控的寡聚和结合以及蛋白质和DNA识别等特性，这将使简单功能系统的设计成为可能。本研究项目旨在利用从头设计的平行异二聚体螺旋螺旋模体作为合成多肽链和环肽的模板。合成策略是基于螺旋链的结合，螺旋链通过硫代酯键连接到要转移的氨基酸和不断增长的肽链。根据天然化学连接的化学原理，肽链从N-端延伸到C-端。硫代酯的连接允许随后的头尾环化，这也是通过盘绕相互作用来调节的。计划开发固相和溶液相合成方法。对于固相合成，通过调节反应缓冲条件来实现对各个反应步骤的控制。然而，为了控制螺旋线圈介导的多肽在溶液中的合成，将开发一种使用正交相互作用的螺旋线圈的螺旋线圈编码。这两种合成策略都将应用于环肽文库的设计和组装。该项目基于合成生物学的研究领域，旨在使用简单的构建块来模拟复杂的生物系统。