Core B: Discovery Core

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ABSTRACT The READDI AViDD Center (READDI-AC) will create new broad spectrum direct acting antiviral (DAA) drug candidates to treat current and emerging pandemic threats. Discovery Core B will serve as the discovery engine for identification of new inhibitory chemical matter (hits), validation of chemically tractable molecular target sites, and will support the optimization of hits to pharmacological tools (chemical probes) and Leads by MedChem Core D. Together and also with Projects 2-5 and Enzymology Core C, we will feed a pipeline of Lead compounds to the Project teams and industrial partners to complement existing assets. This proposal brings a world-leading team, all affiliated with, or collaborators of, the Structural Genomics Consortium (SGC). The SGC is an open science partnership that supports the pharmacological identification of new drug targets and is a world leader in the generation, characterization, and distribution of high-quality chemical probes – one of the most impactful tools for target validation, and an important early milestone in drug discovery. The SGC uses a protein family (aka target class) approach to drive efficiency in development of chemical probes. Through our strong experience with open science and protein family chemical probe development, Discovery Core B together with MedChem Core D are poised to tackle the READDI-AC portfolio of targets, which spans three main families of viral enzymes: RNA polymerases, RNA helicases, and cysteine and serine proteases. Discovery Core B aims to prime the READI-AC and global DAA drug discovery pipeline by generating high- quality chemical probes that will accelerate the development of innovative direct acting anti-viral drugs. Aim 1. Portfolio creation: The Discovery Core B will work closely with the Enzymology Core C, MedChem Core D and Projects 2-5 to select a portfolio of tractable DAA target sites across the four virus families and three main enzyme target protein families, such that eight target sites enter the hit discovery phase each year. Aim 2. Hit discovery and Validation: The Discovery Core B will use both diversity- and knowledge-based HTS for hit discovery using purified recombinant enzyme in one or more of >10 assay formats. Hits will be validated though a robust workflow to yield a data package (Hit CV) for consideration for further optimization. Aim 3. Hit-to-Probe (H2P) activities. Discovery Core B will support MedChem Core D with rapid execution of assays and X-ray crystallography to support structure-guided SAR of compounds made and/or designed in MedChem Core D. We will also evaluate viral-active compounds for selectivity against related human enzymes. Discovery Core B will deliver at least 12 high-quality Hit CVs every year, for consideration by Adman Core A as starting points for Hit-to-Probe/Lead optimization, and support the Hit-to-Probe activities by the Projects. All chemical probes will be made openly available to the scientific community for use as pharmacological tools.