Supramolecular strategies to target cellular membranes

靶向细胞膜的超分子策略

• 批准号: RGPIN-2021-03128
• 负责人: Schmitzer, Andreea
• 金额: $ 3.5万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=742069
• 关键词: Supramolecular; strategies; target; cellular; membranes

In recent years, there has been increasing interest in identifying small organic compounds that self-assemble and are capable of facilitating the transport of ions across phospholipid membranes. Our program aims to develop novel therapeutics for infectious diseases and cancer via an underexplored route - the control or disruption of ion transport in cellular and organelle membranes. This proposal leverages our groups' expertise in the fundamental chemistry of ion transport to develop new classes of antibiotics and chemotherapeutic agents. Our long-term goal is to acquire a new understanding of how ion transport in phospholipid membranes or more complex media can be exploited to produce new generations of compounds that specifically localize in the membrane and organelles, and effectively kill cells. Our specific focus is the optimization of organic cationic derivatives as selective antimicrobial and antitumor agents, as proposed in the following short-term objectives. Objective 1: The synthesis of biguanides and iminoguanidines and fundamental studies of their ion transport properties, transport selectivity and kinetics. We will study their activity against a broad range of invasive microbial strains in order to correlate ion transport properties to antimicrobial and antibiofilm activity. Objective 2. The study of the proposed ionophores to compromise organelles function as target for the treatment of malignancies and cancer in particular. We will exploit the homeostasis-upsetting potential properties induced by the proposed synthetic ion transporters. The perturbation of intracellular ion and pH levels will be used as an apoptosis trigger. Our goal here is to understand the interplay between the facilitated ion permeation by the synthetic ionophores and the natural transport mechanisms of the cell. Objective 3. We will use organometallic half-sandwich complexes as highly versatile platforms for drug design. We will synthesize and study the antimicrobial and anticancerous properties of IrIII complexes with biguanides and iminoguanidines. Efficient synthetic routes and first-hand experience with diverse families of ionophores developed in our group have the potential to yield new compounds and uncover new applications as antibiotics and anticancer agents. This work is highly likely to yield new ways to deliver and target therapeutics.

近年来，人们对鉴定自组装并能够促进离子穿过磷脂膜的小有机化合物越来越感兴趣。我们的计划旨在通过一种尚未探索的途径-控制或破坏细胞和细胞器膜中的离子转运，开发用于感染性疾病和癌症的新型疗法。该提案利用我们小组在离子转运基础化学方面的专业知识来开发新类别的抗生素和化疗剂。我们的长期目标是对磷脂膜或更复杂介质中的离子转运如何被利用以产生新一代化合物的新认识，这些化合物特异性地定位于膜和细胞器中，并有效地杀死细胞。我们的具体重点是优化有机阳离子衍生物作为选择性抗菌剂和抗肿瘤剂，在以下短期目标中提出。 目标一：双胍和亚氨基胍的合成及其离子迁移性质、迁移选择性和动力学的基础研究。我们将研究它们对广泛的侵入性微生物菌株的活性，以将离子传输特性与抗菌和抗菌膜活性相关联。目标2.研究所提出的离子载体，以损害细胞器功能作为治疗恶性肿瘤和癌症的目标，特别是。我们将利用所提出的合成离子转运蛋白诱导的稳态扰乱电位特性。细胞内离子和pH水平的扰动将用作细胞凋亡触发剂。我们的目标是了解合成离子载体促进离子渗透和细胞自然转运机制之间的相互作用。目标3.我们将使用有机金属半夹心配合物作为药物设计的高度通用的平台。我们将合成并研究铱与双胍和亚氨基胍的配合物的抗菌和抗癌性能。高效的合成路线和我们团队开发的不同离子载体家族的第一手经验有可能产生新的化合物，并发现作为抗生素和抗癌剂的新应用。这项工作极有可能产生新的方法来提供和靶向治疗。