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

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，并与疫苗一起预防感染。我们最近发现了一种高效的广谱抗病毒药物thapsigargin(TG)，它是位于细胞器内质网(ER)上的一种钙泵的特异性抑制剂，可能会改变治疗人类主要呼吸道病毒：冠状病毒(包括导致新冠肺炎的SARS-CoV-2)、流感病毒和呼吸道合胞病毒的游戏规则。与传统的直接作用抗病毒药物不同，TG以宿主为中心的作用机制降低了出现耐药突变的可能性，这是治疗高度突变的RNA病毒的一个明显优势。冠状病毒、流感病毒和呼吸道合胞病毒也是动物(包括牛、猪和家禽)的全球病原体。家畜的抗病毒开发落后于人类的抗病毒开发，尽管它在保护动物健康和生产力方面具有潜在的好处。鉴于未来的大流行很可能是由动物引起的，即发生动物传人(人畜共患病)和反向人畜共患病(人与动物之间)的传播，抗病毒药物，如甘油三酯及其衍生物，可能在治疗和控制人类和动物的重要病毒感染方面发挥关键作用。因此，我们在这项建议中的目标是通过产生具有更大抗病毒效力的新的二次衍生物来增强TG的影响和商业意义，用于动物和人类。我们已经证实，甘油三酯具有口服抗病毒活性，它可以转化为有限数量的酯水解物和侧链氧化代谢物。我们假设一个或多个这样的TG代谢物是具有增强的抗病毒活性的新结构。为此，我们建议对甘油三酯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物，合成已鉴定的主要代谢物，并表征合成的代谢物的抗病毒活性，以产生最有希望的甘油三酯衍生物(S)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(与直接针对病毒的传统抗病毒药物相反)，这些药物可以在整体的“同一健康”方法中采用，以控制人类和动物病毒。该项目的成果可能在全球范围内对治疗和控制对人类和动物具有重要意义的RNA病毒感染产生深远影响。

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.