Triangle

 

Collage of humans, chickens, and a pig

 

Our mission   |   Addressing a regional and global need   |   How promising are our host-centric antivirals?   |   Mechanisms of broad-spectrum action   |   Development pipeline status   |   Commercial opportunities and intellectual property

 

Our mission

We have developed a groundbreaking class of host-centred semi-synthetic antivirals which can be used to treat or prevent a range of virus infections across human and veterinary medicine.

These antivirals can be conveniently administered orally or parenterally to treat endemic infections, such as those caused by influenza A virus (IAV), coronavirus and respiratory syncytial virus (RSV). On a global scale, they could safeguard against new epidemic/pandemic outbreaks where specific vaccines are not immediately available. 

We welcome engagement with potential collaborators, partners and investors to accelerate delivery of these invaluable assets.

antiviral medicine
 

 


Addressing a regional and global need

There is an unmet need for effective antivirals to treat major viral infections, including those of SARS-CoV-2, IAV and RSV. The current portfolio of antivirals is limited and offers little assurance of protection against a future pandemic.

The few effective respiratory antivirals in use or in development are typically directed at specific viruses; for instance, PF-07321332 (Pfizer’s Paxlovid = PF-07321332 [nirmatrelvir] with ritonavir), a SARS-CoV-2 antiviral, specifically targets coronavirus 3CL protease only with no or little effect expected against other groups of viruses.

Inevitably, use of such virus-targeting antivirals has the unintended consequence of selecting for virus resistance that will limit clinical usefulness, as exemplified by influenza antivirals, oseltamivir and baloxavir marboxil (Lampejo, 2020; Imai et al., 2020), a situation not dissimilar to antimicrobial resistance but on an accelerated timescale. A host-centric (host-directed) antiviral, which makes the cellular environment incompatible with virus replication, would address limitations in virus specificity and reduce the likelihood of emergence of drug resistance.

 

three viruses, RSV, flu virus, SARS-CoV-2
 

How promising are our host-centric antivirals?

Laboratory

We are developing a first-in-class family of semi-synthetic host-centric antivirals, inspired by the plant molecule thapsigargin (TG), with improved efficacy and safety profiles against major human and veterinary RNA viruses. Our host-centric approach triggers multiple innate antiviral responses that target a virus at multiple steps of its life cycle, effectively blocking virus replication. Their advantages over virus-directed antivirals are:

  1. their ability to inhibit multiple viruses (broad-spectrum), thus enabling versability of deployment, including utility against co-viral infections,
  2. the apparent lack of active selection for virus resistance, and
  3. by ensuring early effective treatment and achieving shorter recovery time, they will save lives and reduce the burden on outpatient clinics and hospitals during an epidemic or a pandemic.
 

 

Mechanisms of broad-spectrum action

We have good insights into the mechanisms of antiviral action of TG and its drug-like analogues. TG, a sesquiterpene lactone, is an irreversible inhibitor of the sarcoplasmic/endoplasmic reticulum calcium (Ca2+) ATPase (SERCA). TG mediated inhibition of SERCA prevents replenishment of the ER Ca2+ pool, triggering (i) store operated calcium entry (SOCE), an influx of extracellular Ca2+ ions into the cytosol, and (ii) ER stress and the unfolded protein response (UPR). Both processes culminate in a highly effective antiviral state capable of inhibiting multiple virus families, including human (e.g. IAV, RSV and SARS-CoV-2) and veterinary (e.g. bird flu viruses and feline infectious peritonitis virus [FIPV]) RNA viruses (Al-Beltagi et al., 2021a; Al-Beltagi et al., 2012b; Goulding et al., 2020).

The points of inhibition vary across viruses; IAV is inhibited post-translationally while RSV and coronaviruses are inhibited at the transcriptional level. SERCA inhibition and UPR appear to be shared with analogues of TG displaying broad spectrum antiviral activity.   

A feature of our semi-synthetic antivirals is that they induce elevated expression of type I and III interferons (IFNs) and other antiviral cytokines. UPR activation of IFN response, and impaired translation and post-translational modification of viral proteins are some of the key mediators of the analogues’ antiviral activities. SOCE-dependent increase in cytosolic Ca2+ may inhibit intracellular localisation of viral proteins as TG impaired IAV nucleoprotein import into the nucleus. 

Development pipeline status

Inspired by TG, we have created a library of second-generation semi-synthetic  antivirals  of which different representative molecules exhibit improved drug-like properties and safety whilst retaining antiviral efficacy against a range human and veterinary RNA viruses.

A major problem of all virus-targeting antivirals, such as oseltamivir, is the emergence of virus resistance which rapidly reduces their usefulness (Leung et al., 2024). Host-centric antivirals are much less susceptible to virus resistance since virus mutations cannot readily overcome its dependency on host cell functions. We previously detected no IAV resistance to TG after 10 serial cell passages (Goulding et al., 2020). Fig. 1 further demonstrated the distinct advantage of host-centric antivirals in not actively promoting virus resistance. We found no resistance of feline infectious peritonitis virus (FIPV), a feline coronavirus, to BO-65, a novel exemplar antiviral analogue, after 10 serial cell passages in sub-optimal antiviral concentration. In contrast, after 10 passages of FIPV in sub-optimal concentration of remdesivir, a nucleoside analogue used in clinical FIP, the resulting passage 10 FIPV were completely resistant to 1.0 μM remdesivir.

Our broad-spectrum antivirals could provide a key line of defence against future pandemics. IAV has been responsible for multiple pandemics in humans and panzootics in other species, as exemplified by the recent spillover of avian H5N1 influenza virus in wild and domestic birds to mammals (Peacock et al., 2024). We have identified compounds with potent activity against multiple influenza virus subtypes across different species, including bird flu virus (Fig. 2).

Viruses in blue
 

 

Fig1

Fig. 1. Exemplar analogue BO-65 and TG at sub-optimal antiviral concentration did not induce FIPV resistance after 10 serial cell passages.  CRFK cells were infected FIPV (strain DF2) at 0.2 MOI in infection medium (DMEM supplemented with 1 % P/S) for 2 h, washed with PBS and replaced with fresh medium (DMEM supplemented with 1 % P/S and 2 % FCS) containing sub-optimal concentrations of TG, BO-65 or remdesivir at 0.93 nM, 2.28 nM and 31.1 nM, respectively, for 24 h after which media from infected cells (P1) were collected, spun and used to infect the next round of freshly seeded CRFK cells. This process was repeated to generate P10 spun media. (A) CRFK cells were infected with stock FIPV (P0) at 0.2 MOI, washed with PBS after 2 h and incubated for 24 h in the presence of 1 µM TG, 1 µM T1, 1 µM remdesivir or DMSO control. (B) Likewise, CRFK cells were infected with equal volumes of P10 media containing virus for 2 h, washed with PBS and incubated for 24 h in the presence of 1 µM TG, 1 µM T1, 1 µM remdesivir or DMSO control. Viral RNA was extracted from 140 μl of spun media using the QIAamp Viral RNA Kit (Qiagen) and quantified by real-time, one-step RT-PCR (QuantiFast SYBR Green, Qiagen). Significance determined by two-way ANOVA, relative to the untreated control, on normalised data.

Fig2

Fig. 2. Anti-avian influenza virus activity of semi-synthetic antivirals in vitro and in ovo. (A) DF-1 cells were infected with H6N1 virus at 1.0 MOI for 2 h before the infection medium (OptiMEM supplemented with 1 % P/S and 200 ng/mL TPCK trypsin) was replaced and the cell incubated in IM supplemented B125 at 2, 0.4, 0.08, 0.016 or 0.0032 uM for 24 h. (B) Ten day old dekalb white chicken eggs were simultaneously infected with a genetically modified highly pathogenic avian influenza virus (AIV09 with PR8 HA and NA) and treated with E173 at the indicated concentration (µg/kg), n=5/group. 10 mM stock suspended in DMSO was diluted in PBS and injected into the allantoic fluid. Allantoic fluid was collected 48 h post infection. (A, B) Viral RNA extracted from spun cell culture supernatant or the allantoic fluid (QIAamp Viral RNA minikit, QIAGEN) and virus copy number quantified by one step RT-qPCR (QuantiNova, QIAGEN). Significance determined by one-way ANOVA, relative to the untreated control.


Commercial opportunities and intellectual property

Annually, there are 3–5 million clinically critical influenza infections worldwide and 300,000 to 500,000 ensuing deaths. Global death toll from COVID-19 is in excess of 7 million (April 2024). Thus, human costs from these two viruses alone, in terms of lives, suffering and economic hardship, are staggering. Our market research estimates that the global market size of an effective antiviral drug to be around £3 bn/year. However, where acute clinical need arises as seen in the COVID-19 pandemic, this can increase substantially (e.g. Paxlovid is estimated to have generated $20 bn in 2022). The market value of a broad-spectrum antiviral that is effective against a range of current and future respiratory viral infections can be expected to be much higher than any existing antiviral market share. Additionally, there is potentially an attractive veterinary antiviral market for companion and production animals.

Presently, the UoN has two TG-related patents that are being prosecuted in the US and Europe. The use of TG, its analogues, and method of SERCA inhibition in antiviral therapy is claimed by PCT/GB2019/050977 (priority date 5th April 2018). The use of TG and its closely related analogues, including composition of a small selection of derivatives is claimed by PCT/GB2020/052479 (priority dates 9th Oct 2019 and 20 March 2020). A third patent filing based on the creation and application of novel antiviral molecules (composition of matter) has been recently filed in the UK.

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