Luminescent Host Molecules for Multisite Recognition of Polyphosphate Anions

用于多磷酸根阴离子多位点识别的发光主体分子

• 批准号: EP/S032339/1
• 负责人: Stephen Butler
• 金额: $ 31.51万
• 依托单位: Loughborough University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS032339%2F1
• 关键词: Luminescent; Host; Molecules; Multisite; Recognition

The search for new drugs often begins with high-throughput screening of lead compounds followed by determination of mode of action of the potential drug and measurements of selectivity and potency. Many drugs act by inhibiting enzyme activity, therefore, to increase confidence in the selection of lead drug compounds it is crucial that pharmaceutical companies have robust, affordable assays to measure enzyme activity accurately. Enzymes that consume and produce nucleoside polyphosphate anions represent a major target in cancer drug discovery. This will enable the best drug candidates to be identified before they enter expensive animal and human testing.The majority of existing enzyme assays require expensive, unstable antibodies or chemically modified reagents, which are time consuming to prepare and require special care in handling. The high cost of these reagents and time required to validate the assays places a significant strain on the drug development process. In addition, these assays are restricted to single 'end-point' measurements, which limits our understanding of the mode of action of a new drug. This increases the risk of a drug candidate passing the early development stages, only to fail at a later, more expensive stage. In order to increase productivity earlier in the drug discovery process, a low-cost method for real-time monitoring of enzyme activity is urgently needed.The aim of this project is to develop molecular probes that bind reversibly to specific nucleoside polyphosphate anions (e.g. adenosine diphosphate) that are produced during pharmaceutically important enzyme reactions. Upon binding to the anion, the probe will provide a luminescent signal that precisely indicates the activity of the enzyme in real-time. The probes will be used to directly measure the production of polyphosphate anions common to several important enzyme classes (kinases, GTPases, glycosyltransferases), eliminating the need for expensive antibodies or chemically modified reagents. The proposed molecular probes have enormous potential to reduce the cost and time required to conduct high-throughput screening assays. They will provide a vital step towards the rapid, accurate determination of enzyme kinetics and mechanism. This will enable better selection and validation of new drug candidates at an early stage in drug discovery, reducing effort pursuing compounds destined to fail in the more lengthy and costly phases of animal and human testing.

新药的研究通常始于先导化合物的高通量筛选，然后确定潜在药物的作用模式并测量选择性和效力。许多药物通过抑制酶活性发挥作用，因此，为了增加选择先导药物化合物的信心，制药公司必须有可靠的、负担得起的测定方法来准确测量酶活性。消耗和产生核苷多磷酸阴离子的酶代表了癌症药物发现的主要目标。这将使最好的候选药物在进入昂贵的动物和人体试验之前得到鉴定。大多数现有的酶测定需要昂贵的、不稳定的抗体或化学修饰的试剂，这些试剂制备耗时，并且在处理时需要特别小心。这些试剂的高成本和验证测定所需的时间对药物开发过程造成了重大压力。此外，这些测定仅限于单一“终点”测量，这限制了我们对新药作用模式的理解。这增加了候选药物通过早期开发阶段的风险，只是在后期更昂贵的阶段失败。为了在药物发现过程的早期提高生产率，迫切需要一种低成本的实时监测酶活性的方法，本项目的目的是开发可逆地结合到特定的核苷多磷酸阴离子（如腺苷二磷酸）的分子探针，这些阴离子在药学上重要的酶反应过程中产生。在与阴离子结合时，探针将提供精确地实时指示酶活性的发光信号。这些探针将用于直接测量几种重要酶类（激酶、GTP酶、糖基转移酶）常见的多磷酸盐阴离子的产生，从而无需昂贵的抗体或化学修饰试剂。所提出的分子探针具有巨大的潜力，以减少进行高通量筛选测定所需的成本和时间。它们将为快速、准确地确定酶的动力学和机理迈出重要的一步。这将有助于在药物发现的早期阶段更好地选择和验证新的候选药物，减少在动物和人体试验的更漫长和昂贵阶段中寻求注定失败的化合物的努力。

项目成果

Advances in anion binding and sensing using luminescent lanthanide complexes.

使用发光灯笼型复合物在阴离子结合和传感的进步。

• DOI: 10.1039/d0sc05419d
• 发表时间: 2021-01-26
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Bodman SE;Butler SJ
• 通讯作者: Butler SJ

Sterically demanding macrocyclic Eu(iii) complexes for selective recognition of phosphate and real-time monitoring of enzymatically generated adenosine monophosphate.

• DOI: 10.1039/d1sc05377a
• 发表时间: 2022-03-24
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: Bodman SE;Breen C;Kirkland S;Wheeler S;Robertson E;Plasser F;Butler SJ
• 通讯作者: Butler SJ

Transmembrane Transport of Phosphate by a Strapped Calix[4]pyrrole

带状杯[4]吡咯对磷酸盐的跨膜转运

• DOI: 10.26434/chemrxiv-2023-rlnx4
• 发表时间: 2023
• 作者: Cataldo A

A Chiral Lanthanide Tag for Stable and Rigid Attachment to Single Cysteine Residues in Proteins for NMR, EPR and Time-Resolved Luminescence Studies.

• DOI: 10.1002/chem.202101143
• 发表时间: 2021-09-09
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Herath ID;Breen C;Hewitt SH;Berki TR;Kassir AF;Dodson C;Judd M;Jabar S;Cox N;Otting G;Butler SJ
• 通讯作者: Butler SJ