Enabling Technologies and Drug Discovery: Continuous Flow Processes to Discover Novel Antiviral Inhibitors

Project Information

VIRO-FLOW

Grant agreement ID: 766058

DOI

10.3030/766058

Project closed

EC signature date 21 September 2017

Start date 1 November 2017

End date 31 October 2021

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 743 618,88

EU contribution

€ 743 618,88

Coordinated by

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 2 - VIRO-FLOW (Enabling Technologies and Drug Discovery: Continuous Flow Processes to Discover Novel Antiviral Inhibitors)

Reporting period: 2019-11-01 to 2021-10-31

Summary of the context and overall objectives of the project

The VIRO-FLOW project aimed to integrate the advantages of continuous flow chemistry with in vitro microfluidic bioassay technologies for the fast and efficient discovery of novel and innovative inhibitors of the Hepatitis B Virus (HBV). The efficient production of drugs represents a challenge for society, since we face novel problems such as the expanding elderly population and the need of new chemical entities (NCE) or new molecular entities (NME) for the treatment of various diseases of high prevalence such as Hepatitis B. This programme aimed to contribute to the development of innovative methodologies that would allow more efficient production of new compounds with anti-viral activity, specifically against HBV, for future transfer of technology and knowledge between different sectors with relevant economic impact.

The global objective of this ITN-EID programme was to provide an innovative and high-level training in drug discovery and enabling technologies for 3 Early-Stage Researchers (ESRs), supported by a network of experts in anti-infective therapeutics, specifically virology and bacteriology in AiCuris, a pharmaceutical company; and the Institute of Chemical Research of Catalonia (ICIQ), a research center working on catalysis, with a special focus on sustainability (functionalization of small molecules, renewable energies, new uses for light in chemistry) using an integrated approach. ICIQ is highly committed to knowledge and technology transfer to the chemical, pharmaceutical and energy industrial sectors. When at ICIQ, the students were integrated in the Pericàs Laboratory and the technology development unit ERTFLOW, with ample expertise in flow chemistry.

All three ESRs, successfully completed their training and individual projects leading to the awarding of a PhD title for each one of them. As a direct consequence of the outstanding work and excellent training received, all three fellows have already secured a qualified job in their field of expertise.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The scientific aim of the VIRO-FLOW project was to design a fully automated continuous flow platform to accelerate the hit to lead development of novel and highly efficient Hepatitis B Virus (HBV) inhibitors. This process includes in silico drug design followed by drug synthesis in flow with inline detection of the compound´s chemical properties and biochemical activity.
The ambition of the project was to use the obtained data and automatically evaluate them to calculate the most fitting structures for the next cycle of structure activity relationship (SAR) development. The automatization of the combined chemical and biochemical processes was to lead to an iterative optimization cycle of the biochemical activity for the newly generated compounds. For this, docking studies and in silico library design for the identification of new chemical entities followed by their synthesis in flow were conducted. Subsequent determination of the half-maximal inhibitory concentrations using a miniaturized microfluidic read out system led to the data required for the next cycle of structure activity relationship (SAR) development. All three ESRs were actively involved in the project. All of them were regularly being trained on their soft skills needed for the upcoming responsibilities as PhD’s in an academic or industrial working environment.

Two publications regarding optimized synthesis in flow chemical are under preparation and anticipated for 2022. One publication for the miniaturization of the HBV capsid assembly assay from 384 well to microfluidic was accepted in November 2021.

Regarding the exploitation of results, the consortium has been working on several patent applications.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Infectious diseases caused by pathogenic microorganisms, such as bacteria and viruses continue to pose substantial challenges to public health, despite the considerable effort made and much progress being achieved toward their control. Among these, chronic HBV infection continues to be a significant unmet medical need. Chronic Hepatitis B is a huge global health problem affecting over 350 million people worldwide that can lead to life-threatening health issues, such us liver cirrhosis or hepatocellular carcinoma (liver cancer). Therefore, extensive and high impact research is needed to overcome this situation. In this sense, the encouraging results obtained during the VIRO-FLOW project makes us optimistic to be able to find very active compounds as well as being able to integrate the advantages of continuous flow chemistry with in vitro microfluidic bioassay technologies for the fast and efficient discovery of novel and innovative inhibitors of the Hepatitis B Virus (HBV) at the end of the project. Moreover, drug discovery is one of the most active research fields both at the academic and industrial level. The skills gained by the ESRs during the development of the integrated flow discovery system are transferable to traditional drug discovery (either in an industrial or academic setting). The ESRs have gained skills in enabling technologies such as computational and docking studies, chemical synthesis, microfluidics and flow chemistry, which go well beyond the scope of drug discovery.

The fellows