Oxadiazole grafts in peptide macrocycles

2016年，我们发现了一种大环化反应，它可以快速将容易获得的线状肽转化为具有明确构象的大环。有助于该反应的(N-异氰胺基)三苯基膦后来被命名为“PINC”，以确定磷和异氰化物官能团的存在。这项研究发表在《自然化学》上，随后被《化学与工程新闻》和《科学》报道。在这一发现之后，我们申请了一项专利申请(PCT/CA2016/000234)，该专利描述了环化多肽并同时将恶二唑接枝引入所得到的大环结构的方法。我们还从NSERC获得了市场评估资金，使我们能够保留Adventus Research的服务，后者进行了一项全面的市场评估研究(请参阅所附的85页报告)。当前的I2I应用程序考虑了该报告的主要信息，并将重点放在两个应用程序上，这两个应用程序将进一步降低我们的技术的风险，因为它已经足够成熟。第一个是开发一种改进的PINC衍生物的合成方法。第二个涉及使用PINC产生的多肽大环，以进一步验证我们对新物质组成的方法。为了向前迈进，我们将开展合作活动以生产PINC(与MilLireSigma一起)，启动旨在将PINC用于杂环合成的翻译研究(与Apotex一起)，并评估PINC衍生的大环在药物发现中的潜力(与Encle和Merck一起)。

In 2016, we discovered a macrocyclization reaction that rapidly converts readily accessible linear peptides into macrocycles with well-defined conformation. (N-isocyanimino)triphenylphosphorane, instrumental to this reaction, was later named "Pinc" to identify the presence of phosphonium and isocyanide functionalities. This work was published in Nature Chemistry and was subsequently covered by The Chemical & Engineering News and Science. On the heels of this discovery, we applied for a patent application (PCT/CA2016/000234) that described the method of cyclizing peptides with simultaneous incorporation of an oxadiazole graft into the resulting macrocyclic structures. We also received market assessment funding from NSERC allowing us to retain the services of Adventus Research who carried out a thorough market assessment study (see the 85-page report attached).The present I2I application considers the main messages from that report and focuses on two applications that will further de-risk our technology now that it is sufficiently mature. The first one is to develop an approach to the synthesis of improved derivatives of Pinc. The second one deals with peptide macrocycles produced using Pinc in order to further validate our approach to novel composition of matter. To move forward, we will engage in collaborative activity to produce Pinc (together with MilliporeSigma), initiate translational studies aimed at the use of Pinc toward heterocycle synthesis (together with Apotex), and evaluate the potential of Pinc-derived macrocycles in drug discovery (together with Encycle and Merck).