Development of novel broad-spectrum antiviral compounds for use in animals and humans

开发用于动物和人类的新型广谱抗病毒化合物

• 批准号: BB/W003295/1
• 负责人: Kin-Chow Chang
• 金额: $ 77.92万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW003295%2F1
• 关键词: Development; novel; broad; spectrum; antiviral

The current pandemic highlights the need for effective antivirals to treat active infections, in conjunction with vaccines, to prevent infection. We recently made an important discovery of a highly effective broad-spectrum antiviral thapsigargin (TG), a specific inhibitor of the Ca2+ pump located on the cellular organelle endoplasmic reticulum (ER), that could be a game changer in the treatment of major human respiratory viruses: coronavirus (including SARS-CoV-2 that causes COVID-19), influenza virus and respiratory syncytial virus (RSV). TG's host-centred mechanism of action, as opposed to conventional direct acting antivirals, reduces the likelihood of drug resistant mutants emerging, a distinct advantage for treating highly mutable RNA viruses. Coronavirus, influenza virus, and RSV are also global pathogens of animals (including cattle, pigs and poultry). Antiviral development for livestock lags behind its human counterpart, despite its potential benefits of safeguarding animal health and productivity. Given that future pandemics are likely to be of animal origin, where animal to human (zoonotic) and reverse zoonotic (human to animal) spread take place, antivirals, such as TG and its derivatives, could play a key role in the treatment and control of important viral infections in both humans and animals. Thus, our goal in this proposal is to enhance the impact and commercial significance of TG through the generation of novel secondary derivatives with greater antiviral potency for animal and human use. We have established that TG is orally active as an antiviral, and that it is converted into a limited number of ester hydrolysis and side chain oxidation metabolites. We hypothesise that one or more of such TG metabolites are novel structures with enhanced antiviral activity. To this end, we propose to carry out detailed in vivo pharmacokinetics (PK) analyses of TG to fully determine its metabolites post-absorption, synthesise the main metabolites identified, and characterise the synthesised metabolites for antiviral activities to generate comprehensive cellular PK and antiviral data of the most promising TG derivative(s) for clinical development and commercial exploitation. TG and its derivatives represent a whole new generation of powerful host-centred antivirals (as opposed to conventional antiviral drugs that directly target viruses) that could be adopted in a holistic "One Health" approach to control human and animal viruses. The outcomes of this project could have far-reaching impact on a global scale in the treatment and control of RNA viral infections of human and animal importance.

目前的大流行突出表明，需要有效的抗病毒药物来治疗活动性感染，同时需要疫苗来预防感染。我们最近发现了一种高效广谱抗病毒毒胡萝卜素（TG），这是一种位于细胞器内质网（ER）上的Ca 2+泵的特异性抑制剂，可能会改变治疗主要人类呼吸道病毒的游戏规则：冠状病毒（包括导致COVID-19的SARS-CoV-2），流感病毒和呼吸道合胞病毒（RSV）。与传统的直接作用的抗病毒药物相反，TG的以宿主为中心的作用机制降低了出现耐药突变体的可能性，这是治疗高度突变的RNA病毒的明显优势。冠状病毒、流感病毒和RSV也是动物（包括牛、猪和家禽）的全球性病原体。尽管抗病毒药物在保护动物健康和生产力方面具有潜在的好处，但其在家畜方面的发展仍落后于人类。鉴于未来的大流行很可能是动物源性的，其中发生动物到人（人畜共患病）和反向人畜共患病（人到动物）传播，抗病毒药物，如TG及其衍生物，可以在治疗和控制人类和动物的重要病毒感染中发挥关键作用。 因此，我们在本提案中的目标是通过产生具有更大抗病毒效力的新型二级衍生物来增强TG的影响和商业意义，用于动物和人类使用。我们已经确定，TG是口服活性的抗病毒药物，它被转化为有限数量的酯水解和侧链氧化代谢产物。我们假设一个或多个这样的TG代谢产物是新的结构，具有增强的抗病毒活性。为此，我们建议对TG进行详细的体内药代动力学（PK）分析，以充分确定其吸收后的代谢产物，合成鉴定的主要代谢产物，并对合成的代谢产物进行抗病毒活性鉴定，以生成最有前途的TG衍生物的全面细胞PK和抗病毒数据，用于临床开发和商业开发。TG及其衍生物代表了全新一代强大的以宿主为中心的抗病毒药物（与直接靶向病毒的传统抗病毒药物相反），可以采用整体的“同一健康”方法来控制人类和动物病毒。该项目的成果可能在全球范围内对人类和动物重要的RNA病毒感染的治疗和控制产生深远的影响。