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Developing a screening platform to identify therapeutics targeting SARS- CoV-2's main protease Mpro

Jost G. Vielmetter
Director of Caltech Protein Expression Center

Dr. Vielmetter aims to develop a new screening platform that leverages the expertise of Caltech's protein expression facility to identify small molecule therapeutics targeting Mpro, the main protease of SARS-CoV-2, and a key component of the viral life cycle.

A current approach to accelerate drug development for COVID-19 is to screen existing drugs for their potential to be repurposed as SARS-CoV-2-specific antiviral agents. One attractive drug target is the SARS-CoV-2 Mpro (or 3CLpro) protease, which is required for generating mature viral proteins in the cell, and which has no human protease analog, making it less likely that inhibitors will show toxic side effects. Existing inhibitors of these types of viral proteases from human enteroviruses and feline peritonitis viruses show no significant toxicity in humans or cats, further reinforcing the potential value of this approach. To identify inhibitors against Mpro, Dr. Vielmetter aims to create a screening platform that takes advantage of Caltech's assay automation core including its automated liquid handling robots, high throughput SPR-32 (Surface Plasmon Resonance) instrument, and its expertise expressing proteins that are essential assay reagents for the proposed platform. The core idea is to screen libraries of compounds against a construct that contains a well-characterized Mpro substrate, the octapeptide AVLQSGFR. A negative control reference protein will also be produced using the same protocols. An SPR-32 readout (i.e., decreases in signals) will enable the researchers to identify inhibitors. This assay platform will allow the group to screen approximately 3840 compounds in about 15-20 hours. In this manner, the group could provide a chemical compound screening hub that can serve to test chemical compound libraries including those already at Caltech, or brought to the group by Caltech researchers or external chemistry labs working on COVID-19 initiatives. Dr. Vielmetter has decades of experience building automated screening platforms and his expertise together with the recent acquisition of a high throughput SPR instrument (the first of its kind in the U.S.) position his lab uniquely to carry out the proposed viral protease inhibitor screening project. This screening approach is unique and different from typical protease screens and it has a high likelihood of success as protease SPR assays have been demonstrated to work well in the past.

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For more information, please contact: Hazel Breen, Senior Director of Development