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，人们对鉴定自组装的小有机化合物的兴趣越来越大，并且能够促进离子跨磷脂膜的运输。我们的计划旨在通过一种未充满刺激的途径开发针对传染病和癌症的新型治疗方法 - 控制或破坏细胞和细胞器膜中离子转运。该提案利用我们小组在离子运输基本化学方面的专业知识来开发新的抗生素和化学治疗剂。我们的长期目标是对如何利用磷脂膜中的离子转运或更复杂的培养基中的离子传输进行新的了解，以生产新一代的化合物，这些化合物专门定位在膜和细胞器中，并有效地杀死细胞。我们的具体重点是将有机阳离子衍生物作为选择性抗菌和抗肿瘤剂的优化，如以下短期目标中所提出的那样。 目标1：Biguanides和iniminoguanidines的合成以及其离子运输特性，运输选择性和动力学的基本研究。我们将研究它们对广泛的侵入性微生物菌株的活性，以将离子转运性能与抗菌和抗生素活性相关联。目标2。拟议的离子载体损害细胞器的研究尤其是治疗恶性肿瘤和癌症的目标。我们将利用所提出的合成离子转运蛋白引起的稳态上的潜在特性。细胞内离子和pH值的扰动将用作凋亡触发。我们的目标是了解合成离子载体的促进离子渗透与细胞的自然运输机制之间的相互作用。目标3。我们将使用有机金属半晶体综合体作为药物设计的高度用途平台。我们将合成和研究IRIII复合物与biguanides和iniminoguanidines的抗菌和抗性特性。在我们小组中开发的各种离子载体家族的有效合成路线和第一手经验有可能产生新的化合物并发现新的应用作为抗生素和抗癌剂。这项工作极有可能产生新的方法来交付和靶向治疗剂。