The oral protease inhibitor (PF-07321332) protects Syrian hamsters against infection with SARS-CoV-2 variants of concern

There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer developed PF-07321332 (PF-332), a potent inhibitor of the viral main protease (Mpro, 3CLpro) that can be dosed orally and that is in clinical development. We here report that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and that it can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian Golden hamsters with PF-332 (250 mg/kg, twice daily) completely protected the animals against intranasal infection with the beta (B.1.351) and delta (B.1.617.2) SARS-CoV-2 variants. Moreover, treatment of SARS-CoV-2 (B.1.617.2) infected animals with PF-332 completely prevented transmission to untreated co-housed sentinels. There is an urgent need for anti-virals targeting SARS-CoV-2. One of the most promising viral targets is the main protease of SARS-CoV-2, which is essential for viral replication and has no human analogue. Here, Abdelnabi et al. show that one of the most promising anti-virals (PF-07321332), currently in clinical trials, protects against SARS-CoV-2 alpha, beta and delta variant infection and provide evidence of reduced transmission.

Automated summary

There is an urgent need for potent and selective antivirals against SARS-CoV-2. Pfizer has developed PF-07321332 (PF-332), a powerful inhibitor of the viral main protease (Mpro, 3CLpro), which can be taken orally and is currently in clinical development. In this study, it was found that PF-332 has equal in vitro activity against the four SARS-CoV-2 variants of concern and can completely halt replication of the alpha variant in human airway epithelial cells. The treatment with PF-332 protected Syrian Golden hamsters against infection with the beta and delta variants and prevented transmission of the SARS-CoV-2 (B.1.617.2) variant to untreated co-housed sentinels.