Ultra-rapid lead generation for antiviral drug discovery

Antiviral drugs to treat coronavirus infections are urgently needed as a complement to vaccines and could save millions of lives in the inevitable future pandemics.

This project will design direct-acting inhibitors targeting SARS-CoV-2 that can be developed to broad-spectrum antiviral drugs. We will focus on two viral proteases (PLpro and Mpro), which are essential for replication and ideal drug targets.

The recent determination of 3D structures of PLpro and Mpro enables us to use rational approaches to identify inhibitors.

We will first design novel fragment libraries and perform structure-based virtual screens combined with machine learning to identify starting-points for development of PLpro inhibitors.

Hits confirmed by biophysical and crystallographic screens will be rapidly optimized by exploiting commercial chemical libraries with billions of compounds. Potent drug-like PLpro inhibitors will be evaluated against panels of coronaviruses in cell models.

The second subproject is focused on further optimization of nanomolar Mpro inhibitors with antiviral effect on infected cells that we already discovered using our combined virtual and biophysical screening approach.

Molecular simulations, synthesis, and experimental testing will be performed to identify compounds suitable for evaluation in animal models within two years.

The project is carried out by an interdisciplinary team of research groups in collaboration with drug discovery facilities at SciLifeLab and MAX IV.