The recent success of Ensitrelvir in preventing COVID-19 represents progress in antiviral research that started early in the pandemic. In January 2020, the complete genome sequence of a SARS-CoV-2 strain appeared on a virology forum. It showed that the virus, like SARS-CoV-1, produces most proteins as one long chain later separated by proteases. SARS-CoV-2 has two such enzymes: the main protease (Mpro) responsible for most cuts and the papain-like protease (PLpro) handling three sites at one end. Researchers quickly identified both as promising drug targets. Viruses use host cell materials and machinery, complicating antiviral development compared with bacterial treatments. Bacteria possess unique structures like cell walls that antibiotics can target without harming human cells. Viruses lack such distinctions, so drugs risk affecting healthy cells too. No broad-spectrum antiviral exists, requiring specific designs for individual viruses or related groups. Viral proteins essential to replication yet distinct from human versions make ideal targets. Both SARS-CoV-2 proteases meet this standard. Mpro became the primary focus. Pfizer scientists noted the similarity between SARS-CoV-2 and SARS-CoV-1 Mpro proteins. They had earlier created an intravenous compound, PF-00835231, against the SARS-CoV-1 version but set it aside after that outbreak ended. In 2020 they redesigned it into an oral drug, Nirmatrelvir, completing trials by late 2021. Nirmatrelvir required combination with Ritonavir to slow liver metabolism, yet this pairing risked interactions with heart and blood pressure medicines and caused a bitter taste. Shionogi pursued a computational approach instead, using Mpro structure to simulate binding molecules. Collaboration with Hokkaido University refined a candidate that remained active longer without extra drugs or aftertaste, named Ensitrelvir. It received emergency approval in Japan in November 2022 and full authorization in early 2024. A New England Journal of Medicine study from the SCORPIO-PEP trial with 2,387 participants showed it can also prevent infection after exposure.
