Small molecule analogues (SMAs) of an immunomodulatory helminth product provide a novel approach to dissecting macrophage signal transduction pathways

免疫调节蠕虫产品的小分子类似物 (SMA) 提供了一种剖析巨噬细胞信号转导途径的新方法

• 批准号: BB/E013929/1
• 负责人: William Harnett
• 金额: $ 99.47万
• 依托单位: University of Strathclyde
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE013929%2F1
• 关键词: Small; molecule; analogues; SMAs; immunomodulatory

The basic unit of life is the cell and all living organisms on Earth are made up of one or more of these. In order to survive and function a cell must be able to communicate with its environment and respond to the signals that it receives. Within the human body, cells respond to signals that they receive either when they make contact with other cells or when they interact with molecules such as proteins and hormones, present in fluid components of the body such as blood. These interactions can trigger changes in cells that may ultimately translate into altered functional capability. This is because the interactions activate biochemical pathways ('signal tranduction pathways') in cells and these pathways promote changes in the cell's molecular composition. For example, the cell may start to produce a new protein that bestows on it properties, previously unpossessed. The response of a cell to a signal is dependent on the nature and quantity of the signal and the signal transduction network of the cell responds to and deciphers each signal to produce an appropriate response. Although it is possible for a cell to produce thousands of new proteins, the signal transduction network uses a resticted number of components to facilitate this. Thus the key to understanding how the cell responds to signals is to elucidate which members of the signal transduction pathway are activated in any particular case. The macrophage is a cell that is involved in fighting disease. As a consequence of this, not only does it have to respond to the types of signal referred to above, it responds to signals it receives from infectious agents attempting to invade the body. The signals come in the form of molecules of the pathogens that bind to receptors on the surface of the macrophage. A good example of a type of receptor is the Toll-like family of receptors. These respond to pathogen products by activating signal transduction pathways that ultimately result in the production within the macrophage of a group of molecules called pro-inflammatory cytokines. These molecules are secreted and have an important role in combatting infectious agents. However, their production must be carefully regulated as left unchecked they have the potential to cause more harm than good, as overproduction of these molecules is associated with many chronic inflammatory diseases. The key question that we wish to address is how the macrophage signal transduction network regulates production of individual inflammatory mediators. We have found that a worm pathogen product that we discovered (ES-62) inhibits certain signal transduction pathways in macrophages and certain other cells of the immune system. We have investigated a number of small molecule analogues (SMAs) of ES-62 and found that although some of them possess inhibitory activity, this is often more focussed than that associated with the parent molecule and also differs in target amongst SMAs. Thus it appears to be possible to inhibit production of a particular cytokine and this offers the opportunity to then establish the signalling events underlying regulation of this cytokine. The aim of this project is thus to make a larger number (a 'library') of related SMAs and to test their ability to inhibit pro-inflammatory cytokine responses and thus understand their associated regulation. If successful we will provide novel and important information on how macrophages respond to pathogens. Furthermore, as signalling pathways are highly conserved in evolution, we will advance knowledge at the fundamental level in the fields of cell biology and biochemistry as a whole.

生命的基本单位是细胞，地球上所有的生物都是由一个或多个细胞组成的。为了生存和运作，细胞必须能够与环境沟通，并对它接收到的信号做出反应。在人体内，细胞对它们接收到的信号做出反应，要么是当它们与其他细胞接触时，要么是当它们与蛋白质和激素等分子相互作用时，这些分子存在于身体的液体成分(如血液)中。这些相互作用可以触发细胞的变化，最终可能转化为功能上的改变。这是因为相互作用激活了细胞中的生化通路(信号转导通路)，而这些通路促进了细胞分子组成的变化。例如，细胞可能会开始产生一种新的蛋白质，这种蛋白质赋予它以前没有的特性。细胞对信号的反应取决于信号的性质和数量，细胞的信号转导网络响应并破译每个信号以产生适当的反应。尽管细胞有可能产生数千种新的蛋白质，但信号转导网络使用数量有限的组件来促进这一过程。因此，了解细胞如何对信号做出反应的关键是阐明信号转导途径的哪些成员在任何特定情况下被激活。巨噬细胞是参与抗击疾病的细胞。因此，它不仅必须对上述类型的信号做出反应，而且还对它从试图入侵人体的传染病病原体接收到的信号做出反应。这些信号以病原体分子的形式出现，这些分子与巨噬细胞表面的受体结合。一种受体的一个很好的例子是Toll样受体家族。这些细胞通过激活信号转导通路对病原体产物做出反应，最终导致巨噬细胞内产生一组称为促炎细胞因子的分子。这些分子是分泌的，在对抗感染性病原体方面发挥着重要作用。然而，它们的产生必须受到仔细的监管，因为如果不加以控制，它们可能弊大于利，因为这些分子的过度生产与许多慢性炎症性疾病有关。我们希望解决的关键问题是巨噬细胞信号转导网络如何调节单个炎症介质的产生。我们发现，我们发现的一种蠕虫病原体产物(ES-62)可以抑制巨噬细胞和免疫系统其他某些细胞中的某些信号转导途径。我们已经研究了一些ES-62的小分子类似物(SMA)，发现尽管其中一些具有抑制活性，但这通常比与亲本分子相关的更集中，并且在SMA之间靶标也不同。因此，似乎有可能抑制特定细胞因子的产生，这为随后建立该细胞因子调控的信号事件提供了机会。因此，该项目的目的是建立更多相关的SMA，并测试它们抑制促炎细胞因子反应的能力，从而了解它们的相关调节。如果成功，我们将提供有关巨噬细胞如何对病原体做出反应的新的重要信息。此外，由于信号通路在进化中是高度保守的，我们将在细胞生物学和整个生物化学领域的基础水平上推进知识。

项目成果

Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus.

• DOI: 10.1177/0961203315591031
• 发表时间: 2015-11
• 期刊: Lupus
• 影响因子: 2.6
• 作者: Rodgers DT;Pineda MA;Suckling CJ;Harnett W;Harnett MM
• 通讯作者: Harnett MM

Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.

• DOI: 10.1021/jm401251p
• 发表时间: 2013-12-27
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Al-Riyami L;Pineda MA;Rzepecka J;Huggan JK;Khalaf AI;Suckling CJ;Scott FJ;Rodgers DT;Harnett MM;Harnett W
• 通讯作者: Harnett W

Failure of the Anti-Inflammatory Parasitic Worm Product ES-62 to Provide Protection in Mouse Models of Type I Diabetes, Multiple Sclerosis, and Inflammatory Bowel Disease.

• DOI: 10.3390/molecules23102669
• 发表时间: 2018-10-17
• 期刊: Molecules (Basel, Switzerland)
• 作者: Doonan J;Thomas D;Wong MH;Ramage HJ;Al-Riyami L;Lumb FE;Bell KS;Fairlie-Clarke KJ;Suckling CJ;Michelsen KS;Jiang HR;Cooke A;Harnett MM;Harnett W
• 通讯作者: Harnett W

Small molecule analogues of the immunomodulatory parasitic helminth product ES-62 have anti-allergy properties.

• DOI: 10.1016/j.ijpara.2014.05.001
• 发表时间: 2014-08
• 期刊: INTERNATIONAL JOURNAL FOR PARASITOLOGY
• 影响因子: 4
• 作者: Rzepecka, Justyna;Coates, Michelle L.;Saggar, Moninder;Al-Riyami, Lamyaa;Coltherd, Jennifer;Tay, Hwee Kee;Huggan, Judith K.;Janicova, Lucia;Khalaf, Abedawn I.;Siebeke, Ivonne;Suckling, Colin J.;Harnett, Margaret M.;Harnett, William
• 通讯作者: Harnett, William

The parasitic worm product ES-62 protects against collagen-induced arthritis by resetting the gut-bone marrow axis in a microbiome-dependent manner

• DOI: 10.3389/fitd.2023.1334705
• 发表时间: 2024-01
• 期刊: Frontiers in tropical diseases
• 作者: M. Harnett;J. Doonan;Anuradha Tarafdar;M. Pineda;Josephine Duncombe-Moore;Geraldine Buitrago;Piaopiao Pan;P. Hoskisson;Colin Selman;W. Harnett