Screening of Medicines for Malaria Venture Open Boxes Identifies Potent SARS-CoV-2 Papain-like Protease (PLpro) Inhibitors

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High Resolution Image Download MS PowerPoint Slide The COVID-19 pandemic, caused by SARS-CoV-2, has led to more than 760 million infections and 6.9 million deaths worldwide. While vaccines have played a crucial role in controlling the disease, emerging viral variants pose a threat to their long-term efficacy, highlighting the need for antiviral therapies. To accelerate drug discovery, Medicines for Malaria Venture (MMV) developed open-access compound libraries, including the malaria box, pathogen box, COVID box and, with the drugs for neglected disease initiative, pandemic response box, comprising nearly 1400 drug-like molecules. These resources have been widely used in phenotypic screens to identify potential SARS-CoV-2 inhibitors, but target-based screening remained unexplored, especially for targets such as papain-like protease (PL pro ). Here, we report a target-based screening campaign against SARS-CoV-2 proteases, focusing on both the main protease (M pro ) and PL pro . From this effort, MMV1634397 emerged as a promising PL pro inhibitor (IC 50 = 0.7 μM). Further optimization led to analogs with improved activity such as 5, 10, and 13, with IC 50 values of 0.16, 0.34, and 0.06 μM, respectively. The most potent compound and its isomer also exhibited antiviral activity in ACE2-HeLa cells (EC 50 = 2.9 and 3.7 μM, respectively) with favorable pharmacokinetic properties. Our findings highlight the value of the MMV open-access libraries in accelerating target-based antiviral drug discovery against SARS-CoV-2 and other emerging pathogens.

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