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Rational design of a new class of protease inhibitors for the potential treatment of coronavirus diseases

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Coronavirus main protease (Mpro) is an essential protein in the life cycle of coronaviruses, playing a pivotal role in viral replication of SARS-CoV-2.  Currently there is intense interest in discovering effective inhibitors of SARS-CoV-2 MPro, but it is unclear whether the versions known so far would be safe and effective in treating human coronavirus diseases.  For example, one currently available compound contains an aldehyde reactive group (warhead), but aldehydes are generally considered toxic due to off-target reactions.  Mpro inhibitors that use ketoamide or “Michael acceptor” warheads instead are considered preferable in terms of specificity and stability, but they appear insufficiently effective to be of therapeutic benefit.

Michael Lin (Associate Professor of Neurobiology and Bioengineering at Stanford University) has been working with researchers at Stanford University and Utah State University.  They have developed a ketoamide inhibitor, called ML1000, that suppresses SARS-CoV-2 replication more effectively than previously described ketoamide or Michael acceptor compounds.  And, ML1000 was designed using chemical motifs from drugs with well-established safety profiles in humans.

Assuming that a pre-organized backbone conformation could be beneficial, the team designed new ketoamide-based Mpro inhibitors based on central proline rings.  ML1000 inhibited viral replication in human cells with an EC50 of 0.1 µM, thereby representing the highest-potency non-aldehyde Mpro inhibitor reported to date.

In the absence of an effective vaccine against SARS-CoV-2, antiviral drugs will be needed as the current COVID-10 pandemic continues. Ideally, these drugs could be administered orally so they can be taken in outpatient setting, without requiring hospitalization.

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