I-Corps: Protein Transduction Domain Mimics to Revolutionize Immunology

这项拟议的技术是基于一类聚合物蛋白转导结构域模拟物(PTDM)的发现，该PTDM具有在细胞内传递大量生物分子(小分子、核酸、蛋白质甚至完整的抗体)的独特能力。已经成功地进行了体外和体内(与小鼠模型)的实验，证明了这项技术的有效性。这些分子是通过开环歧化聚合(ROMP)合成的，这种聚合允许在化学组成和结构上保持高保真。这些PTDM不需要将货物共价连接，使这一创新适用于各种生物分子，并且非常易于使用。这一创新为许多细胞内的隔间和功能提供了潜在的途径，从而提供了新的研究和治疗机会。对人体及其高度调控的功能的接受性一直是生物医学科学面临的最大挑战之一。人类基因组和蛋白质组计划极大地有助于阐明人体的许多生物学和分子功能，并通过发现新的细胞靶点来推进疾病的治疗。不幸的是，由于细胞膜缺乏通透性和高选择性，这一重要知识尚未得到充分应用，这使得这些靶标无法获得。这项提案中描述的交付具有使许多新的研究和应用机会成为可能的潜力，特别是但不限于在免疫学领域，在那里最终将有可能操纵迄今无法穿透的T细胞。T细胞在细胞介导的免疫反应中发挥着关键作用，例如对抗感染、癌症和艾滋病毒。与传统的电穿孔和病毒感染相比，以更有效和更安全的方式控制它们的激活的能力将产生巨大的社会和商业影响。

The proposed technology is based on the discovery of a class of polymeric protein transduction domain mimics (PTDMs) with the unique ability to intra-cellularly deliver a large variety of biomolecules (small molecules, nucleic acids, proteins and even whole, intact antibodies). Both in vitro and in vivo (with mouse models) experiments have been successfully performed demonstrating the efficacy of this technology. These molecules are synthesized via Ring-Opening Metathesis Polymerization (ROMP), which allows high fidelity over the chemical composition and structure. These PTDMs do not require covalent attached of the cargo, making this innovation applicable to various biomolecules and extremely easy to use. This innovation gives potential access to many intracellular compartments and functions thus offering new research and therapeutic opportunities.Accessibility to the human body and its highly regulated functions has always been one of the biggest challenges for biomedical sciences. The human genome and proteome projects have greatly contributed to elucidate many biological and molecular functions of the human body and to advance treatment of diseases by discovering new cellular targets. Unfortunately, this important knowledge cannot yet been fully applied because of the lack of permeability and the high selectivity of the cell membrane which makes these targets inaccessible. The delivery described in this proposal has the potential to enable many new research and application opportunities, especially, but not exclusively, in the immunology field where it will finally become possible to manipulate the so far impenetrable T-cells. T-cells play a critical role in cell-mediated immune response, for example against infections, cancer and HIV. The ability to control their activation, in a more efficient and safer way than the traditional electroporation and virus infection, will have a big societal and commercial impact.