Discovery of the Clinical Candidate S‑892216: A Second-Generation of SARS-CoV‑2 3CL Protease Inhibitor for Treating COVID-19
Coronavirus infections are widespread, with symptoms of varying severity depending on the virus and the individual circumstances of the patient. In 2022, Shionogi disclosed the structure of ensitrelvir, an orally bioavailable non-covalent, non-peptidomimetic Coronavirus Main Protease (CoV MPro) inhibitor which is approved for use against COVID-19 in Japan and Singapore. The discovery of ensitrelvir is a story worth reading, beginning from a virtual screening campaign in the midst of the COVID-19 pandemic. They used what scarce structural data on the SARS-CoV-2 MPro that was available at the time in the literature, including structures solved by the Covid Moonshot Consortium.
Viral proteases such as MPro are essential for replication and are considered high quality, clinically validated targets for the treatment of coronaviridae and others. Pfizer’s MPro inhibitor: nirmatrelvir is the active ingredient (API) in the COVID-19 treatment: Paxlovid, which has seen great clinical and commercial success. The notorious drawback to Paxlovid is the use of the PK booster ritonavir, while this provides adequate blood levels of the API, it precludes certain parts of the patient population due to the risk of drug-drug interactions. Since 2022, there has been a flurry of research interest in finding MPro inhibitors that plug this gap by having equivalent or better efficacy than nirmatrelvir without the need for co-dosing of PK boosters and ideally at a lower dose. Pfizer themselves have since disclosed ibuzatrelvir, which is a second-generation variant on nirmatrelvir that doesn’t require ritonavir co-dosing. We have also contributed to this research effort as part of ASAP (https://asapdiscovery.org/), recently disclosing ASAP-0017445, which is an orally bioavailable pan-CoV MPro inhibitor.