Design, synthesis and testing of oxidatively robust inhibitors for cysteine proteases in SARS2 virus and poliovirus

According to Johns Hopkins University data, as of August 2022, COVID caused by the Severe Acute Respiratory Syndrome 2 (SARS2) virus has infected 589 million worldwide (4.14 million in Canada) and caused 6.43 million deaths (43,440 in Canada). Vaccines and health measures have helped contain infections, but many still become sick, and elderly or immunocompromised individuals are at risk for severe disease. Antiviral treatment is approved with orally active Paxlovid, which is a combination of nirmatrelvir that prevents viral replication and ritonavir that inhibits its metabolism. Unfortunately, ritonavir also inhibits metabolism of many other drugs, making correct dosages unclear. This is especially true for at risk populations that may be medicated for other conditions, such as cholesterol reduction by statins. Ideally, only a single drug that blocks viral proliferation with greater resistance to human metabolism would be administered to avoid undesired side effects with other medications. Nirmatrelvir and related antivirals (eg GC376) target an enzyme essential for viral replication, namely the 3CL protease that cuts a large protein initially generated into pieces used to make new virus. Human metabolism of nirmatrelvir occurs mainly in intestine and liver through oxidation by cytochrome P450 3A4. This enzyme metabolizes about 50% of all medicines and is blocked by ritonavir. Interestingly, some antivirals that inhibit the key protease of coronaviruses such as SARS2 also block the process in poliovirus (a picornavirus). Although ~92% of the population is immunized against polio, there are rare disease outbreaks such as one in 2022 in New York. We propose to make new viral protease inhibitors that are longer-lived in the body, can stop SARS2 replication and also block poliovirus in infected individuals. This work will provide antiviral drugs that can be given without ritonavir, are resistant to human metabolism and will suppress the virus in infected individuals.