A novel glucocorticoid and androgen receptor modulator reduces viral entry and innate immune inflammatory responses in the Syrian Hamster model of SARS-CoV-2

摘要: Since its initial discovery in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of COVID19, has spread worldwide and despite significant research efforts, treatment options remain limited. Replication SARS-CoV-2 lung is associated with marked infiltration macrophages activation innate immune inflammatory responses triggered, part, by heightened production interleukin-6 (IL-6) that recruits lymphocytes to site infection amplify tissue injury. Antagonists glucocorticoid androgen receptors have shown promise experimental models COVID19 clinical studies, because cell surface proteins required for viral entry, angiotensin converting enzyme (ACE2) transmembrane serine protease (TMPRSS2), are transcriptionally regulated these receptors. We therefore postulated (GR) receptor (AR) antagonist, PT150, would reduce infectivity prevent injury Syrian golden hamster model COVID19. Animals were infected intranasally 2.5 x 104 TCID50/ml equivalents (strain 2019-nCoV/USA-WA1/ 2020) PT150 was administered oral gavage at 30 100 mg/Kg/day a total 7 days. then examined days 3, 5 post-infection (DPI) histopathology, load regulating initiation progression infection. Results studies indicated administration decreased replication lung, as well expression ACE2 TMPRSS2 protein. Hypercellularity driven macrophage dramatically PT150-treated animals, damage IL-6. Molecular modeling suggested binds co-activator interface ligand binding domain both AR GR thereby acts an allosteric modulator transcriptional repressor Phylogenetic analysis across multiple species permissive revealed high degree sequence identity maintained species, including human, suggesting mechanism action therapeutic efficacy observed hamsters likely be predictive positive outcomes patients. strong candidate further development variants SARS-CoV-2.