WP2 From new hits to early lead

This work package, coordinated by Dr. Patrick Chaltin (KU Leuven), aims to identify and evaluate new hits using our three parallel screening tracks

  • high-throughput library screening (HTS) (~100k compounds)
  • hits identified or developed for specific viral targets
  • hits identified via machine-learning methods

At the start of PANVIPREP (2024), hit compounds for all targeted virus families will be selected. Data packages will be generated and evaluated based on the activity, selectivity, and other properties of hits.

In 2025, the portfolio of hits will be ranked (irrespective of the virus they inhibit) based on their developability into a novel antiviral drug in the context of pandemic preparedness. Two hit series will be prioritized for hit-to-early lead development. The primary objectives will be to obtain insight into their molecular mechanism of action and in vivo proof of concept of their antiviral activity. In addition, at least two other hit series will be selected as backup series and progress in the hit-to-early lead process. Remaining hits may be deprioritized, but will be transferred to WP3 & WP4 to be used as tool compounds/chemical probes to conduct mechanistic studies and unravel their mode of action.

WP2 will drive the hit-to-early lead efforts to obtain more potent and selective compounds with broad-spectrum antiviral activity and optimized pharmacokinetics (PK) properties. Hit identification/enrichment and hit-to-lead activities will be supported by Computer-Aided Drug Discovery (CADD) approaches, also known as “in silico” methods. Computer-based tools will be used to rationalize and predict the physical, chemical, biological and pharmacokinetics (PK) properties of compounds. Those range from the simple calculation of topological descriptors to elaborate models based on machine learning/artificial intelligence (ML/AI). Additionally, these approaches can be used to support the Mini-Projects of WP4.

Compounds endowed with potent antiviral activity promising in vitro ADME-TOX / PK properties, and an acceptable target profile will be synthesized in sufficient amounts to perform proof-of-concept studies in an animal model for the respective viruses. In case the compound series has a novel mechanism-of-action, this will then be validated at the same time.

Automated BSL-3 compound facility at KU Leuven.