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

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 main viral protease (Mpro, 3CLpro) that can be dosed orally; the compound is in clinical development. We demonstrate that PF-332 exerts equipotent in vitro activity against the four SARS-CoV-2 variants of concerns (VoC) and can completely arrest replication of the alpha variant in primary human airway epithelial cells grown at the air-liquid interface. Treatment of Syrian 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. The trough drug concentration at this efficacious dose were above the in vitro efficacious concentrations.

Nelfinavir markedly improves lung pathology in SARS-CoV-2-infected Syrian hamsters despite a lack of an antiviral effect (preprint)

In response to the ongoing COVID-19 pandemic, repurposing of drugs for the treatment of SARS-CoV-2 infections is being explored. The FDA-approved HIV protease inhibitor Nelfinavir is one of the drugs that has been reported to inhibit in vitro SARS-CoV2 replication. We here report on the effect of Nelfinavir in the Syrian hamster SARS-CoV-2 infection model. Although treatment of infected hamsters with either 15 mg/kg BID or 50 mg/kg BID Nelfinavir [for four consecutive days, initiated on the day of infection] did not reduce viral RNA loads nor infectious virus titres in the lungs (as compared to the vehicle control at the end of treatment) the drug markedly improved virus-induced lung pathology at doses that were well tolerated. Yet, a massive interstitial infiltration of neutrophils was observed in the lungs of treated (infected and uninfected) animals. The protective effect of Nelfinavir on SARS-CoV-2-induced lung pathology that is unrelated to an antiviral effect warrants further exploration in the context of the treatment of COVID-19.

Environmentally-induced mdig is a major contributor to the severity of COVID-19 through fostering expression of SARS-CoV-2 receptor NRPs and glycan metabolism (preprint)

The novel {beta}-coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has infected more than 101 million people and resulted in 2.2 million death worldwide. Recent epidemiological studies suggested that some environmental factors, such as air pollution, might be the important contributors to the mortality of COVID-19. However, how environmental exposure enhances the severity of COVID-19 remains to be fully understood. In the present report, we provide evidence showing that mdig, a previously reported environmentally-induced oncogene that antagonizes repressive trimethylation of histone proteins, is a master regulator for SARS-CoV-2 receptors neuropilin-1 (NRP1) and NRP2, cathepsins, glycan metabolism and inflammation, key determinants for viral infection and cytokine storm of the patients. Depletion of mdig in bronchial epithelial cells by CRISPR-Cas-9 gene editing resulted in a decreased expression of NRP1, NRP2, cathepsins, and genes involved in protein glycosylation and inflammation, largely due to a substantial enrichment of lysine 9 and/or lysine 27 trimethylation of histone H3 (H3K9me3/H3K27me3) on these genes as determined by ChIP-seq. These data, accordingly, suggest that mdig is a key mediator for the severity of COVID-19 in response to environmental exposure and targeting mdig may be one of the effective strategies in ameliorating the symptom and reducing the mortality of COVID-19.