3C is a not-for-profit Community Interest Company (CIC) led by a group of experts with proven backgrounds in antiviral drug discovery, in both pharma and biotech. We propose a new approach to emerging viruses, designed to ensure the world community is better prepared for the epidemics caused by viruses which will inevitably follow COVID-19. Our focus is on developing inhibitors of the viral RNA polymerase complex of coronaviruses, including COVID-19, as a demonstration of a more efficient approach to the problem.
COVID-19 & Emerging Viruses
The ‘COVID-19 pandemic’ is an example of a virus emerging from animals and their adaptation to infect and cause disease in human hosts. These events have occurred throughout history, but with apparent increased frequency over the last few decades. For example, in the previous 15 years, there has been four significant viral epidemics or pandemics – Swine Flu, plus three members of the coronavirus family: SARS, MERS and COVID-19. Over the same time period, other outbreaks have occurred including those caused by Ebola, Zika and Chikungunya viruses. Fortunately, these outbreaks remained restricted in their spread and did not cause pandemics. This increase in the frequency and/or spread of these emerging infections can be attributed to many important factors:
- Environmental changes
- Climate change
- An increase in global travel
- An increase in global wealth/emergence of mega-cities
Current Reaction To The Emergence Of A Viral Threat
When a new virus does emerge, there is the inevitable clamour for a new vaccine or a drug to control the infection. Existing drugs may be pressed into a clinical trial. Any such drug is unlikely to be very clinically effective against a virus for which it was not designed. The diversity of viral genomes restricts the development of “broad spectrum” antiviral agents.
Recent epidemics give some clue as to where we may see future emerging viral threats:
- Ebola and related viruses
- Corona Viruses: SARS, MERS and COVID-19
- Nipah & Hendra viruses
- Zika virus
- Influenza virus
3C’s Alternative Approach To Emerging Infections: Viral Polymerases As A Universal Target
Viral polymerases are an attractive common target for all these emerging viruses. We propose developing a comprehensive plan to ensure the world is never in the current situation again.
This requires a new strategy of developing poised antiviral compounds.
Currently, each time a threat emerges, programmes begin from a zero base. Because of the cost and time to fully develop a drug within the commercial sector, there is huge inertia about the initiation of discovery programmes. In our experience pharmaceutical companies are not likely to focus their efforts on preparing for the ‘it might never happen’ scenario.
However, pharma is keen to be involved once clinical candidates emerge. Academic programmes are ideal for long term research efforts but do not generally have the expertise, resources and experience to succeed in developing lead molecules. We propose a switch to the discovery of poised antiviral leads for virus families with strong pandemic potential, led by a focussed team of industry experts.
The Initial Project – Identifying Inhibitors Of SARS-CoV-2 RNA Polymerase Complex
In the case of coronaviruses, there is a 98% amino acid sequence identity between the polymerase proteins between SARS and SARS-CoV-2. If a SARS-CoV-2 polymerase inhibitor is identified and developed, it would likely have activity against SARS and other members of the coronavirus family. Suitably optimised inhibitors could be stored and used against a newly emergent coronavirus epidemic.
Our strategy is to take attractive lead molecules through early preclinical development to an IND ready state and then to select suitable late-stage development partners. Profits to 3C from any such partnering deal would be immediately recycled into identifying a compound for other potential pandemic culprits. And a particular focus on synthetic costs will ensure therapies are available globally.
Progress To Date
We began by establishing a collaboration with a screening partner; the SARS-CoV-2 laboratory at the University of Leuven. We validated our approach using their live virus screen and two small sets of compounds. Remdesivir was used as a positive control. We were encouraged to find immediate success identifying hits.
Our next step was to establish contacts with three companies who have libraries containing suitable compound types and have screened a total of approaching 10,000 of these compounds. Initial hits were confirmed using 8-point IC50 assays. This work has identified a range of lead series which inhibit SARS-CoV-2 with good potency and low toxicity.
Based on this chemical knowledge, chemistry has begun and we have identified more potent derivatives of the initial molecules. We are establishing a range of collaborations to expedite the detailed study of mode of action and to accelerate preclinical development. Leading UK Universities (UCL and Oxford) are amongst our first partners, as well as Monash University in Australia.
In conclusion, the scientific progress has been rapid and exciting. The data we have generated has exceeded our expectations. With these promising results to hand we are entering the next phase in moving these lead molecules into clinical candidates. Rapid commitment of new funds will enable us to maintain this momentum.