A Synthetic Biology Approach to Engineering Protein Assemblies for use in Vaccine Design

新兴的生物纳米技术科学旨在利用生物自组装的原理，结合结构和生化知识，设计出纳米级的大分子结构，并将其应用于医学和相关领域。最近在使用异源、非天然融合蛋白和能够形成大的、稳定的、多聚体组件的工程连接物方面取得了进展。这种结构的发展为常规组件的设计带来了令人兴奋的可能性，这些组件可以用作展示来自感染性细菌的多个抗原副本的平台。然后，这些组件将以类似于病毒样颗粒的方式有效地激发保护性免疫反应，病毒样颗粒已经被广泛用作疫苗。要设计这样的结构、表达和分离它、验证组装并证明其作为疫苗的有效性需要一系列技能，从计算和基于合成生物学的设计、蛋白质生物化学、结构生物学和免疫学。这一多学科项目将检验这种新方法开发脑膜炎双球菌脑膜炎疫苗的潜力。这在发展中国家和发达国家是一种严重的疾病；控制的尝试只取得了有限的成功，部分原因是B组血清生物的表面蛋白抗原与引起脑膜炎奈瑟菌的细菌有相当大的差异。设计的含有脑膜炎抗原的人工组件将被设计、生产和测试其刺激抗体产生的能力，这些抗体能够杀死脑膜炎奈瑟菌。最终，这种方法可能会带来一种开发疫苗的新方式。Callaghan等人。(2011)感染。伊蒙。79、2810-2818 Lai等人。(2013)J.Am化学。SoC。135,7738-7743 Saleem等人。(2013)Plos One。8 DOI：e5674610.1371 King等人。(2014)自然510,103-108

The emerging science of Bionanotechnology aims to use the principles of biological self-assembly, combined with structural and biochemical knowledge, to engineer nanoscale macromolecular structures with applications in medicine and related fields. Advances have been made recently in using heterologous, non-natural fusion proteins with engineered linkers that are capable of forming large, stable, multimeric assemblies. The development of such structures raises exciting possibilities for the design of regular assemblies which could be used as platforms for the display of multiple copies of antigens from an infectious bacterium. These assemblies would then be effective at eliciting a protective immune response, in a similar fashion to virus-like particles, which are already in widespread clinical use as vaccines. To design such a structure, express and isolate it, verify the assembly and demonstrate its effectiveness as a vaccine requires a range of skills, from computation and synthetic biology-based design, protein biochemistry, structural biology and immunology. This multidisciplinary project will examine the potential of this novel approach to develop a vaccine against meningococcal meningitis. This is a serious disease in developing and developed countries; attempts at control have met with only limited success, partly due to the considerable variation in surface protein antigens from serogroup B organisms from the causative bacterium, Neisseria meningitidis. Designed artificial assemblies, with incorporated meningitis antigens, will be designed, produced and tested for their ability to stimulate the production of antibodies which are capable of killing N. meningitidis. Ultimately, this approach could lead to a new way of developing vaccines. Callaghan et al. (2011) Infect. Immun. 79, 2810-2818Lai et al. (2013) J. Am. Chem. Soc. 135, 7738-7743 Saleem et al. (2013) Plos One. 8 doi:e5674610.1371King et al. (2014) Nature 510, 103-108