Repurposing and/or reactivating disused clinically relevant medical therapies

重新利用和/或重新激活废弃的临床相关医疗疗法

• 批准号: MR/T020415/1
• 负责人: Jennifer Hiscock
• 金额: $ 155.43万
• 依托单位: University of Kent
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT020415%2F1
• 关键词: Repurposing; reactivating; disused; clinically; relevant

Since humans first discovered that plants and biological extracts could be used to treat ailments, many thousands of assorted therapies have been developed to treat illness and disease. In modern times these therapies include, but are not limited to, small molecule synthetic compounds, large biological proteins, and peptides. Developing new drugs and therapies is expensive, and takes a long time. Decisions about which drugs should be developed for clinical use are often made about market value and potential profit as companies seek to recoup their investment. Over time, a considerable number of these therapies have become disused. One reason for this is due to cellular resistance, that is, the biological system that a therapy targets evolves and becomes resistant to treatment. Increasing resistance to antimicrobials, antibiotics and anti-cancer drugs is predicted to cause a global health crisis, that will return us to a medical dark-age. In 2010 the economic impact of cancer was found be $1.16 trillion (1.5% of GDP). Cancer is difficult to treat because normal healthy cells and cancerous tumour cells are similar. This, combined with increasing anti-cancer drug resistance and the high cost of effective treatments, means that global mortality figures are only set to rise from estimated deaths of 9.6 million in 2018. The increasing prevalence of antimicrobial resistance (AMR) in bacteria has been well advertised, however what is not so widely known is that AMR has now been identified to every antimicrobial currently marketed. By 2050 it is estimated that 10 million people per year will die from AMR diseases.I will address this global health crisis by working to reactivate drugs that have already been approved for use but have been discarded. I will produce a technology that will revitalise currently approved medical therapies by increasing their efficacy, while simultaneously developing novel drug candidates.To achieve this, I have invented a novel class of molecules that can stick selectively to the surface of specific types of target cell (such as cancer or bacteria). This 'sticking' process produces molecular gateways into the target cell which either result in cell death or enable drugs to pass effectively from the outside to the inside of the cell, increasing permeability of a drug towards the target cell. This type of work is interdisciplinary, and therefore requires a team that are able to work at the interface of chemistry, biology, pharmacy and social science. Additionally, I want to find out how a team like this can be supported to create and make discoveries, and how it can work effectively.Although currently targeted to produce novel therapeutic weapons in the fight against AMR and cancer, the development of this technology has the potential to regenerate and increase the activity for a much wider range of currently approved but disused medical therapies. It may also make drugs effective for treating a wider variety of diseases or infections where entry into the cell is the limiting factor, increasing the number and scope of illnesses that can be treated by the same drug. Therefore, this molecular innovation represents an attractive alternative to the high costs and long-timeframes associated with the conventional identification and development of a single novel drug.

自从人类第一次发现植物和生物提取物可以用来治疗疾病以来，已经开发了成千上万种各种各样的疗法来治疗疾病。在现代，这些疗法包括但不限于小分子合成化合物、大生物蛋白和多肽。开发新的药物和疗法是昂贵的，而且需要很长时间。公司在寻求收回投资时，往往根据市场价值和潜在利润来决定应该开发哪些药物用于临床。随着时间的推移，相当多的这些疗法已经被废弃了。其中一个原因是由于细胞耐药性，即治疗目标的生物系统进化并对治疗产生耐药性。据预测，对抗菌剂、抗生素和抗癌药物耐药性的增加将导致全球健康危机，这将使我们回到医学的黑暗时代。2010年，癌症对经济的影响达到1.16万亿美元（占GDP的1.5%）。癌症很难治疗，因为正常的健康细胞和恶性肿瘤细胞是相似的。这一点，再加上抗癌药物耐药性的增加和有效治疗的高成本，意味着全球死亡率数字只会在2018年估计的960万死亡人数的基础上上升。细菌中抗菌素耐药性（AMR）的日益普遍已经得到了很好的宣传，但不那么广为人知的是，目前市场上销售的每一种抗菌素现在都已被确定为抗菌素耐药性。据估计，到2050年，每年将有1000万人死于抗菌素耐药性疾病。我将通过努力重新激活已经批准使用但已被废弃的药物来应对这一全球卫生危机。我将开发一种技术，通过提高目前已批准的医学疗法的疗效来振兴它们，同时开发新的候选药物。为了实现这一目标，我发明了一类新的分子，它们可以选择性地粘附在特定类型的目标细胞（如癌症或细菌）的表面。这种“粘附”过程产生进入靶细胞的分子通道，要么导致细胞死亡，要么使药物有效地从细胞外部进入细胞内部，增加药物对靶细胞的渗透性。这种类型的工作是跨学科的，因此需要一个能够在化学、生物学、药学和社会科学的界面上工作的团队。此外，我想知道如何支持这样的团队进行创造和发现，以及如何有效地工作。虽然目前的目标是生产对抗抗菌素耐药性和癌症的新型治疗武器，但这项技术的发展有可能使更广泛的目前批准但已废弃的医疗疗法再生并增加其活性。它还可以使药物有效地治疗更多种类的疾病或感染，在这些疾病或感染中，进入细胞是限制因素，从而增加了同一种药物可以治疗的疾病的数量和范围。因此，这种分子创新代表了一种有吸引力的替代方案，与传统的单一新药鉴定和开发相关的高成本和长时间框架。

项目成果

An Area-Specific, International Community-Led Approach to Understanding and Addressing Equality, Diversity, and Inclusion Issues within Supramolecular Chemistry.

• DOI: 10.1002/anie.202015297
• 发表时间: 2021-05-17
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Caltagirone C;Draper ER;Hardie MJ;Haynes CJE;Hiscock JR;Jolliffe KA;Kieffer M;McConnell AJ;Leigh JS
• 通讯作者: Leigh JS

Supramolecular self-associating amphiphiles (SSAs) as enhancers of antimicrobial agents towards Escherichia coli (E. coli).

• DOI: 10.1039/d1ra00998b
• 发表时间: 2021-03-01
• 期刊: RSC advances
• 影响因子: 3.9
• 作者: Boles JE;Ellaby RJ;Shepherd HJ;Hiscock JR
• 通讯作者: Hiscock JR

Anionic Self-Assembling Supramolecular Enhancers of Antimicrobial Efficacy against Gram-Negative Bacteria

• DOI: 10.1002/adtp.202200024
• 发表时间: 2022-03-31
• 期刊: ADVANCED THERAPEUTICS
• 影响因子: 4.6
• 作者: Boles, Jessica E.;Williams, George T.;Hiscock, Jennifer R.
• 通讯作者: Hiscock, Jennifer R.

Towards the Prediction of Antimicrobial Efficacy for Hydrogen Bonded, Self-Associating Amphiphiles.

• DOI: 10.1002/cmdc.202000533
• 发表时间: 2020-11-18
• 期刊: ChemMedChem
• 影响因子: 3.4
• 作者: Allen N;White LJ;Boles JE;Williams GT;Chu DF;Ellaby RJ;Shepherd HJ;Ng KKL;Blackholly LR;Wilson B;Mulvihill DP;Hiscock JR
• 通讯作者: Hiscock JR

Establishing the selective phospholipid membrane coordination, permeation and lysis properties for a series of 'druggable' supramolecular self-associating antimicrobial amphiphiles.

• DOI: 10.1039/d2sc02630a
• 发表时间: 2022-08-24
• 期刊: CHEMICAL SCIENCE
• 影响因子: 8.4
• 作者: Boles, Jessica E.;Bennett, Charlotte;Baker, Jennifer;Hilton, Kira L. F.;Kotak, Hiral A.;Clark, Ewan R.;Long, Yifan;White, Lisa J.;Lai, Hin Yuk;Hind, Charlotte K.;Sutton, J. Mark;Garrett, Michelle D.;Cheasty, Anne;Ortega-Roldan, Jose L.;Charles, Mark;Haynes, Cally J. E.;Hiscock, Jennifer R.
• 通讯作者: Hiscock, Jennifer R.