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

当前的大流行突出表明，需要使用有效的抗病毒药物治疗活动性感染，并结合疫苗预防感染。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Ca2+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（包括引起COVID-19的SARS-CoV-2），流感病毒和呼吸道合胞病毒（RSV）。与传统的直接作用抗病毒药物不同，TG以宿主为中心的作用机制降低了耐药突变体出现的可能性，这是治疗高度可变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）的全球性病原体。家畜抗病毒药物的开发落后于人类抗病毒药物的开发，尽管它具有保护动物健康和生产力的潜在益处。鉴于未来的流行病很可能是动物源性的，发生动物对人（人畜共患）和反向人畜共患（人对动物）的传播，抗病毒药物，如甘油三酯及其衍生物，可在治疗和控制人类和动物中的重要病毒感染方面发挥关键作用。因此，我们在本提案中的目标是通过生成具有更强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。我们已经确定TG作为抗病毒药物具有口服活性，并且它被转化为有限数量的酯水解和侧链氧化代谢物。我们假设一种或多种这样的TG代谢物是具有增强抗病毒活性的新结构。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物，合成鉴定出的主要代谢物，并对合成的代谢物进行抗病毒活性表征，从而为临床开发和商业开发提供最有前途的TG衍生物的全面细胞PK和抗病毒数据。甘油三酯及其衍生物代表了全新一代以宿主为中心的强大抗病毒药物（与直接针对病毒的传统抗病毒药物相反），可以在“同一个健康”的整体方法中采用，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人类和动物RNA病毒感染的治疗和控制产生深远的影响。

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.