Synthesis and SAR Studies of Coronavirus Main Protease Inhibitors

Bailey, Patrick

Student Work

Synthesis and SAR Studies of Coronavirus Main Protease Inhibitors

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SARS-CoV-2 has been extremely impactful the last few years, with more than 774 million confirmed cases and more than 7 million deaths worldwide since the beginning of the pandemic. Highly effective vaccines were made available and have been a great help to many, but SARS-CoV-2 is capable of rapid mutation that makes vaccines less effective with time. Because of this, it is critical to develop drugs to minimize the negative impacts of this virus. One of the most promising targets for these drugs is the virus's main protease (Mpro/3CLpro), a cysteine protease responsible for driving the viral replication process after the virion enters the cell. Nirmatrelvir (the active component of Pfizer’s Paxlovid) is one of the most well-known anti-SARS-CoV-2 drugs, and it forms a reversible covalent bond to Mpro's catalytic Cys145 using a cyano group “warhead”. Nirmatrelvir uses a γ-lactam as a glutamine mimic, essential for Mpro’s substrate recognition, with three other regions that studies have shown to be variable. This paper examines the use of 2-hydroxypyridine and pyrazine groups in one region, which were hypothesized to fit Mpro’s subsite particularly well and form pi-stacking interactions with Mpro’s catalytic His41, as well as the use of a D-Phe motif in the other regions, which is similar to a potent L-Phe-D-Phe motif seen in the literature, with hopes to increase selectivity for Mpro. Our research shows that the D-Phe motif greatly decreased the molecule’s potency combined with a modified proline moiety, but the 2-hydroxypyridine group, while less favorable than nirmatrelvir’s bicyclic proline motif, has a lot of potential for future SAR studies.

This report represents the work of one or more WPI undergraduate students submitted to the faculty as evidence of completion of a degree requirement. WPI routinely publishes these reports on its website without editorial or peer review.

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