Abstract
Despite significant research efforts, treatment options for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain limited. This is due in part to a lack of therapeutics that increase host defense to the virus. Replication of SARS-CoV-2 in lung tissue is associated with marked infiltration of macrophages and activation of innate immune inflammatory responses that amplify tissue injury. Antagonists of the androgen (AR) and glucocorticoid (GR) receptors have shown efficacy in models of COVID-19 and in clinical studies because the cell surface proteins required for viral entry, angiotensin converting enzyme 2 (ACE2) and the transmembrane protease, serine 2 (TMPRSS2), are transcriptionally regulated by these receptors. We postulated that the GR and AR modulator, PT150, would reduce infectivity of SARS-CoV-2 and prevent inflammatory lung injury in the Syrian golden hamster model of COVID-19 by down-regulating expression of critical genes regulated through these receptors. Animals were infected intranasally with 2.5 × 104 TCID50/ml equivalents of SARS-CoV-2 (strain 2019-nCoV/USA-WA1/2020) and PT150 was administered by oral gavage at 30 and 100 mg/Kg/day for a total of 7 days. Animals were examined at 3, 5 and 7 days post-infection (DPI) for lung histopathology, viral load and production of proteins regulating the progression of SARS-CoV-2 infection. Results indicated that oral administration of PT150 caused a dose-dependent decrease in replication of SARS-CoV-2 in lung, as well as in expression of ACE2 and TMPRSS2. Lung hypercellularity and infiltration of macrophages and CD4+ T-cells were dramatically decreased in PT150-treated animals, as was tissue damage and expression of IL-6. Molecular docking studies suggest that PT150 binds to the co-activator interface of the ligand-binding domain of both AR and GR, thereby acting as an allosteric modulator and transcriptional repressor of these receptors. Phylogenetic analysis of AR and GR revealed a high degree of sequence identity maintained across multiple species, including humans, suggesting that the mechanism of action and therapeutic efficacy observed in Syrian hamsters would likely be predictive of positive outcomes in patients. PT150 is therefore a strong candidate for further clinical development for the treatment of COVID-19 across variants of SARS-CoV-2.
Highlights
Following the emergence of a number of idiopathic cases of severe pneumonia in December 2019 in Wuhan, China, deep sequencing of lower respiratory samples from these patients revealed a novel beta-coronavirus that was identified as the causative agent of COVID-19 [1]; Zhu et al [2]
Hamsters treated with PT150 at 30 and 100 mg/Kg/day did not show a statistically significant difference in body weight from control hamsters at day 5 post-infection, at which the maximal extent of body weight loss is observed in Syrian hamsters infected with SARS-CoV-2 and treated with vehicle only (Figure 1B)
Of the few treatments that are available, many are the result of repurposing efforts and have low efficacy and limited experimental characterization surrounding the direct mechanisms of action against SARS-CoV-2
Summary
Following the emergence of a number of idiopathic cases of severe pneumonia in December 2019 in Wuhan, China, deep sequencing of lower respiratory samples from these patients revealed a novel beta-coronavirus that was identified as the causative agent of COVID-19 [1]; Zhu et al [2]. The four genera of these viruses – Alphacoronavirus, Beta-coronavirus, Gamma-coronavirus, and Delta-coronavirus – share a highly conserved genome organization comprising a large replicase gene followed by structural and accessory genes. The organization of the SARS-CoV-2 coronavirus genome is arranged from the 5’-leader-UTR, replicase, S (spike), E (envelope), M (membrane), N (nucleocapsid) to the 3’ UTR poly (A) tail [6]. The spike protein is a surface glycoprotein that mediates virus-cell membrane fusion through interaction with the ACE2 receptor and subsequent proteolytic cleavage by TMRPSS2 [7]. Proteolytic cleavage of the spike protein enables membrane fusion and entry into the host cell in complex with the ACE2 receptor [9]
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