#	Pagina
attuale pagina	/open-h2020/projects/212130/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - VIRO-FLOW (Enabling Technologies and Drug Discovery: Continuous Flow Processes to Discover Novel Antiviral Inhibitors)

Teaser

Summary

The VIRO-FLOW project aims 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 aims to contribute to the development of innovative methodologies that 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 is 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 will by integrated in the PericÃ s Laboratory and the technology development unit ERTFLOW, with ample expertise in flow chemistry.

Work performed

During the period covered by the present report, the work performed within the Viro-Flow project involves several docking studies and in silico library design for the identification of new chemical entities followed by their synthesis in flow has been conducted. Moreover, the 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. In particular from the virtual screening, five compounds with activity in a biochemical assay were identified from three hundred and forty eight commercially available molecules. Based on this, other two small molecule focused libraries were designed leading to novel entities with improved activity. On the other hand, SAR exploration of the most active scaffold was performed. The multistep synthesis of the analogue compounds was developed and conducted under continuous flow. Active compounds were tested and investigate for their mode of action in order to differentiate between two different modes of inhibition, achieving already with high potency. Additionally the synthesis of other different library of compounds with strategic bioisosteric replacement has been evaluated and the optimization of the synthesis in continuous flow is ongoing. Finally, the biochemical assay for the determination of antiviral activity of compounds interfering with HBV capsid assembly has been able to be miniaturized and transferred to a microfluidic read out device showing high reproducibility and comparable EC50 values after several repetitions.

Final results

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 so far during this period of 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 transferrable to traditional drug discovery (either in an industrial or academic setting). The ESRs will also gain 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.