Turning "Impossible" into Delivered: The Story Behind our Contribution to the COVID Moonshot Project

We are proud to share a recent success story that showcases the power of collaboration, scientific excellence and determination: our contribution to the development of a pre-clinical drug candidate¹ - a highly effective antiviral for coronaviruses developed by the COVID Moonshot project and AI-driven Structure-enabled Antiviral Platform (ASAP).

Emerging pathogens such as SARS, MERS, Ebola, Zika and SARS-CoV-2 have repeatedly shown that new viral threats can appear unpredictably, and global health systems often lack anti-viral drugs that can rapidly be deployed when they do. COVID Moonshot is a non-profit, open-science, global collective of scientists committed to discovering safe, affordable and globally accessible antiviral drugs against COVID-19 and future viral pandemics.

We are thrilled to have played a significant role in bringing this candidate, ASAP 0017445, from early concept towards the clinic.

Chemistry: Achieving what others said was impossible

Our team of chemists carried out process research & development activities on the 20-step synthesis, to enable a ½ kg scale-up of ASAP-0017445 within just 10 months. A feat that other CMDO/CROs had informed the client was impossible with the budget and tight time frame!

Highlights of our chemistry contribution include:

• Executing a challenging alkylation step at scale: We safely performed the key alkylation step to give the sterically congested spirocyclic quaternary chiral carbon centre using NaH/DMF on 2.1 kg scale.
• Developing a salt resolution strategy: Development of a salt resolution to purge an unwanted diastereoisomer, which meant the use of chiral prep SFC could be avoided; this one change saved the manufacturing team four weeks, saved over £25,000 in manufacturing costs and reduced PMI ten-fold.
• Scaling carbonylation: Processed 6 kg through a carbonylation step using our 7.8 L autoclave.
• Optimization of a notoriously capricious Knoevenagel reaction: Through mechanistic understanding and identification of by-products, we were able to maximize yields and achieve consistency².
• Development strategy for rapid progress: We carried out development work on the final steps towards a range of possible final targets at risk. This allowed us to move quickly once the final target structure had been decided.

ADME: Accelerating Design-Make-Test cycles

Alongside the chemistry effort, to support rapid design-make-test cycles, our ADME department implemented a high-throughput screening strategy. Compounds were routinely assessed using in vitro assays including MDCK permeability, hepatocyte stability and plasma protein binding across multiple species.

Data were generated and interpreted rapidly, enabling medicinal chemists to prioritize compounds with well-balanced ADME profiles rather than focusing solely on potency. In parallel, the ADME team played a central role in the execution and interpretation of in vivo pharmacokinetic studies, delivering timely PK data and integrating these findings with in vitro results to provide critical insights into absorption, bioavailability and dose–exposure relationships, thereby supporting informed compound progression decisions.

Impact

We are proud to have played our part in the journey of ASAP-0017445 from Concept to Clinic. Delivery of 500 g of ASAP-0017445 enabled the client to carry out toxicology studies ahead of nominating the compound as their pre-clinical candidate. The work was possible with the expertise, dedication and fortitude of a large portion of our scientific team involved across both our Chapel-en-le-Frith and Sandwich sites.

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References

1.     Open-science approach delivers a promising pre-clinical candidate for broad-spectrum coronavirus antiviral | DNDi

2.     Expedient Synthesis of 1‐Oxo‐1,2,3,4‐Tetrahydroisoquinoline‐4‐Carboxylates- Bilenko - European Journal of Organic Chemistry - Wiley Online Library

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