Efficacy and pharmacokinetics of novel THF compounds against major veterinary coronaviruses

There is an acute and unmet need for effective antivirals for veterinary diseases. Coronaviruses cause significant disease in both companion and livestock animals, from feline infectious peritonitis virus (FIPV) in cats, infectious bronchitis virus (IBV) in poultry, and transmissible gastroenteritis virus (TGEV) in pigs. These viral diseases significantly impact animal welfare and, in livestock animals, productivity. Antivirals may be used in lieu of a vaccine or to complement existing vaccination strategies where there may be inadequate efficacy with available vaccines. Our host-centric antivirals trigger multiple innate immune responses that target a virus at multiple steps of its life cycle. Their advantages over virus-directed antivirals are (i) their ability to inhibit multiple viruses (broad-spectrum), thus enabling versatility of deployment and (ii) the apparent lack of active selection for virus resistance. Inspired by natural compound thapsigargin (TG), we have generated a compound library of semi-synthetic antivirals with a range of antiviral activities. These have been screened for activity against viruses of significance in human medicine, including influenza virus, SARS-CoV-2 and respiratory syncytial virus. We have identified a subset of compounds, novel tetrahydrofuran (THF) compounds, with vastly improved drug-like characteristics and improved safety profiles. Our project goal is to expand their application into veterinary medicine, enhancing their impact and commercial significance. We hypothesise that several candidates of our novel THF series of antivirals are highly effective against animal coronaviruses, demonstrated by in vitro, in ovo, and in vivo models, possess strong safety and drug-like profiles, and do not promote virus resistance. Thus, we will develop promising lead compounds based on antiviral efficacy against different animal coronaviruses, and characterise their toxicity/safety and drug-like profiles to pave the way towards clinical use against coronavirus infection in companion and production animals. Aim 1: To identify strong antiviral candidates from the novel THF series against a spectrum of coronaviruses from different animal species. Objective 1.1. Screen THF antivirals against TGE virus in vitro. Objective 1.2. Screen THF antivirals against IBV in ovo. Aim 2: To determine in vitro drug metabolism and pharmacokinetics (DMPK) properties of selected THF antivirals, and to assess the in vivo pharmacokinetics (PKs) and tolerability of selected candidates, resulting in the shortlisting of 1-2 most promising lead antiviral compounds. Objective 2.1. Screen in vitro DMPK properties of THF antivirals to assess drug-ability. Objective 2.2. Conduct in vivo pharmacokinetics (PK) of selected antiviral candidates in mice. Objective 2.3. Perform in vivo dose range-finding study of 1-2 most promising antiviral candidates in mice. Aim 3: To demonstrate antiviral efficacy of 1-2 highly promising antiviral candidates in vitro, in ovo and in vivo. Objective 3.1. Characterise in vitro and in ovo antiviral activity against FIPV, IBV and TGEV. Objective 3.2. Determine in vivo efficacy of up to two lead THF antivirals in mice against model coronavirus MHV-A59. In summary, we seek to develop our novel semi-synthetic THF antivirals for use in the treatment of coronavirus infection in companion and production animals. The making of bespoke veterinary antivirals against coronavirus infections, with the added prospect of broad-spectrum antiviral applicability, will be unprecedented in veterinary medicine and can have profound impact on the promotion of animal health and welfare. Effective treatment and shorter recovery time of infected animals will save animal lives, improve animal wellbeing, and, for production animals, reduce economic losses from infections that hitherto are untreatable.