Systematic development of novel peptide-derived inhibitors for methyl-regulatory enzymes

通过与Zim公司及其子公司Nuvobio（一家总部位于渥太华的本地公司，对分子工具和肽抑制剂感兴趣）的直接合作，该提案将使合作伙伴组织能够有效地设计和商业化细胞活性和靶向特异性抑制剂。这些商业化资源的开发将使蛋白质功能和细胞过程反卷积的研究更加广泛。由于蛋白质功能障碍通常被认为是疾病进展的关键驱动因素，Zim已经认识到迫切需要开发可用于研究基础蛋白质生物学的策略。因此，需要开发必要的工具来研究细胞背景下的蛋白质功能。通过我们的合作研究，我们将能够激发以肽为中心的新型生物技术产品的增长，最终使加拿大人和加拿大经济受益。这项初步的合作工作将集中在两类蛋白质的肽抑制剂的产生上，这些蛋白质调节赖氨酸甲基化的化学蛋白质修饰，特别是赖氨酸甲基转移酶（KMT）和去甲基化酶（KDM）酶。赖氨酸甲基化在过去十年中作为一种蛋白质修饰出现，在许多细胞过程中具有广泛的意义，并且几种KMT和kdm的功能障碍是已知的癌症驱动因素。考虑到赖氨酸甲基化参与越来越多的不同生物过程，甲基化事件的研究在理解基本细胞生物学方面越来越重要，这也许并不奇怪。因此，人们对了解这些甲基调节酶的生物学特性非常感兴趣，然而，只有少数KMT和KDM抑制剂被发现或开发出来。此次合作解决了这一问题，并代表了扩大KMT和KDM抑制剂商业市场的重大努力。这项NSERC联盟合作研究计划的目标是开发KMT和KDM酶的靶向特异性肽抑制剂，作为甲基赖氨酸蛋白质组研究的工具。

Through a direct partnership with Zim Corp. and their subsidiary Nuvobio, a local Ottawa-based company with interest in molecular tools and peptide inhibitors, this proposal will allow the partner organization to efficiently design and commercialize cell-active and target-specific inhibitors. The development of these commercialized resources will enable the broader study of protein function and the deconvolution of cellular processes. As protein dysfunction is commonly hallmarked as critical drivers of disease progression, Zim has recognized that there is an urgent need to develop strategies that can be used to study basic protein biology. As a result, there is a need for the development of tools that are necessary to study protein function in a cellular context. Through research enabled by our collaborative effort, we will be able to spark growth in novel, peptide-centric biotechnology products that will ultimately benefit Canadians and the Canadian economy. This initial collaborative work will focus on the generation of peptide-inhibitors for two classes of proteins that regulate a chemical protein modification referred to as lysine methylation, specifically, lysine methyltransferase (KMT) and demethylase (KDM) enzymes. Lysine methylation has emerged in the last decade as a protein modification with expanding implications in a number of cellular processes, and the dysfunction of several KMT and KDMs are known drivers of cancer. Given the involvement of Lys methylation in a growing number of different biological processes, perhaps it is not surprising that the study of methylation events has been increasingly important in understanding basic cellular biology. As a result, there is a great interest to understand the biology of these methyl-regulatory enzymes, however, only a handful of KMT and KDM inhibitors have been discovered or developed. This collaboration addresses this issue and represents a significant effort towards expanding the commercial market of KMT and KDM inhibitors. The goal of this proposed NSERC Alliance collaborative research program is to develop target-specific peptide inhibitors of KMT and KDM enzymes as tools for the study of the methyl-Lys proteome.