Poster presentation abstract by Rebecca Hertzman – Masters Student at the Weizmann Institute of Science

This is an abstract of the poster presentation by Rebecca Hertzman – an Australian Masters Student at the Weizmann Institute of Science – which she presented at the Ilanit Conference in Eilat in February 2023.

Although the response of the scientific community towards treatment of COVID-19 has been unprecedentedly rapid, relatively little effort was devoted to development of small molecule anti-virals. The magnitude of the pandemic highlights the need to employ all tools at hand to begin the drug discovery process for viruses prior to transition into pandemic. Inspired by the COVID Moonshot project, the AI-Driven Structure-Enabled Antiviral Platform (ASAP) intends to accelerate medicinal chemistry via an open-access, machine-learning based pipeline from target identification to fragment-to-lead screening to optimisation to preclinical development. 

Our team explores covalent targeting approaches directed towards the serine protease NS2B-NS3 that enables viral replication of mosquito-borne flaviviruses Zika, Dengue and West Nile, and the main protease of coronaviruses such as SARS-CoV-2 and MERS. Proteases are promising drug targets for covalent approaches due to their highly nucleophilic active site, allowing in theory for inhibitors with superior selectivity and potency. Utilising high-throughput screening of electrophilic fragment libraries against recombinant proteases, we are able to identify fragments that bind to proteases and explore structure-activity relationships for development covalent inhibitors. Inhibitors are tested biochemically using protease inhibition assays to assess potency before being taken forwards for antiviral assays in infected cells. In parallel to electrophilic fragment screening, we are also conducting a variety of virtual, empirical and phage-based screening techniques to explore the entire chemical landscape. Our ultimate goal is to have Phase II ready compounds, before the emergence of the next pandemic, that would allow immediate clinical trials and rapid pandemic response when needed.