Click here to close Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly. We suggest using a current version of Chrome, FireFox, or Safari.
XB-ART-60193
PLoS Pathog 2023 Aug 01;198:e1011328. doi: 10.1371/journal.ppat.1011328.
Show Gene links Show Anatomy links

Post-infection treatment with the E protein inhibitor BIT225 reduces disease severity and increases survival of K18-hACE2 transgenic mice infected with a lethal dose of SARS-CoV-2.

Ewart G , Bobardt M , Bentzen BH , Yan Y , Thomson A , Klumpp K , Becker S , Rosenkilde MM , Miller M , Gallay P .


Abstract
The Coronavirus envelope (E) protein is a small structural protein with ion channel activity that plays an important role in virus assembly, budding, immunopathogenesis and disease severity. The viroporin E is also located in Golgi and ER membranes of infected cells and is associated with inflammasome activation and immune dysregulation. Here we evaluated in vitro antiviral activity, mechanism of action and in vivo efficacy of BIT225 for the treatment of SARS-CoV-2 infection. BIT225 showed broad-spectrum direct-acting antiviral activity against SARS-CoV-2 in Calu3 and Vero cells with similar potency across 6 different virus strains. BIT225 inhibited ion channel activity of E protein but did not inhibit endogenous currents or calcium-induced ion channel activity of TMEM16A in Xenopus oocytes. BIT225 administered by oral gavage for 12 days starting 12 hours before infection completely prevented body weight loss and mortality in SARS-CoV-2 infected K18 mice (100% survival, n = 12), while all vehicle-dosed animals reached a mortality endpoint by Day 9 across two studies (n = 12). When treatment started at 24 hours after infection, body weight loss, and mortality were also prevented (100% survival, n = 5), while 4 of 5 mice maintained and increased body weight and survived when treatment started 48 hours after infection. Treatment efficacy was dependent on BIT225 dose and was associated with significant reductions in lung viral load (3.5 log10), virus titer (4000 pfu/ml) and lung and serum cytokine levels. These results validate viroporin E as a viable antiviral target and support the clinical study of BIT225 for treatment and prophylaxis of SARS-CoV-2 infection.

PubMed ID: 37549173
PMC ID: PMC10434922
Article link: PLoS Pathog


Species referenced: Xenopus laevis
Genes referenced: ano1 calu kcnip2 krt18.1
GO keywords: ion channel activity [+]

Disease Ontology terms: Coronavirus infectious disease

Article Images: [+] show captions
References [+] :
Al-Zaidan, The expression of hACE2 receptor protein and its involvement in SARS-CoV-2 entry, pathogenesis, and its application as potential therapeutic target. 2021, Pubmed