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Proof-of-Concept Studies With a Computationally Designed Mpro Inhibitor as a Synergistic Combination Regimen Alternative to Paxlovid

Papini et al., PNAS. 2024.

https://www.pnas.org/doi/abs/10.1073/pnas.2320713121?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%20%200pubmed

As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection. Results indicate favorable pharmacological properties, efficacy, and drug synergy, as well as complete recovery from subsequent challenge by SARS-CoV-2, establishing Mpro61 as a promising potential preclinical candidate. Supported by ORIP (R24OD026440, S10OD021527), NIAID, and NIGMS.

A Multidimensional Metabolomics Workflow to Image Biodistribution and Evaluate Pharmacodynamics in Adult Zebrafish

Jackstadt et al., Disease Models & Mechanisms. 2022.

https://www.doi.org/10.1242/dmm.049550

The evaluation of tissue distribution and pharmacodynamic properties of a drug is essential but often expensive in clinical research. The investigators developed a multidimensional metabolomics platform to evaluate drug activity that integrates mass spectrometry–based imaging, absolute drug quantitation, in vivo isotope tracing, and global metabolome analysis in zebrafish. They validated this platform by evaluating whole-body distribution of the anti-rheumatic agent hydroxychloroquine sulfate and its impact on the systemic metabolism of adult zebrafish. This work suggests that the multidimensional metabolomics platform is a cost-effective method for evaluating on- and off-target effects of drugs. Supported by ORIP (R24OD024624) and NIEHS.