https://journals.plos.org/plospathogens/article?id=10.1371/journa...

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011328

pretty powerful discussion points

‘The high efficacy of BIT225 treatment even when treatment was delayed for 24 or 48 hours after infection is notable, as monoclonal antibodies and other direct-acting antiviral agents have previously shown significant losses of efficacy when treatment initiation was delayed in lethal SARS-CoV mouse models. Treatment of SARS-CoV infection in the MA15 mouse model with GS-5734 (Remdesivir) showed outcomes similar to vehicle control when treatment started on Day 2 after infection [41]. Early treatment start was required for differentiation from vehicle, but even that could not fully protect mice from weight loss during treatment [41]. Similarly, treatment with EIDD-2801 (Molnupiravir) in this mouse model showed a significant loss of efficacy when treatment was delayed by 24 or 48 hours after infection [42]. When mice implanted with human lung tissue and infected with SARS-CoV-2 were treated with Molnupiravir, the treatment efficacy measured as a reduction of lung virus titres was lower when treatment was started at 48 hours after infection, as compared to earlier treatment starts [43]. Reports on treatment of hACE2 transgenic K18 mice infected with SARS-CoV-2 with Remdesivir, Molnupiravir, Nirmatrelvir or the 3CL protease inhibitor GC376 demonstrate the difficulty of protecting SARS-Cov-2 infected K18 mice from weight loss in this challenging mouse model of severe virus-induced pathogenicity. A 5-day treatment starting 6 hours after infection with Remdesivir, Molnupiravir or Nirmatrelvir protected < 50% of mice from death and could not protect mice from weight loss during treatment. A combination of Molnupiravir and Nirmatrelvir could achieve 80% survival [44]. A 10-day treatment with a deuterated analog of GC-573 starting 24 hours after infection of K18 mice with SARS-CoV-2 could protect all mice from death, but mice still showed significant weight loss during treatment [45].

BIT225 was initially designed as an HIV-1 Vpu viroporin inhibitor [8,37,38], and subsequently, demonstrated activity against Bovine viral diarrhea virus (BVDV) and Hepatitis C virus (HCV) p7 viroporins [9]. BIT225 has shown antiviral activity against both HIV-1 and HCV in the clinic, as well as potential to reverse adverse viral-induced immunopathogenesis [39,40]. SARS-CoV-2 may be particularly sensitive to viroporin inhibition, considering that this virus encodes not only one but several viroporin-like proteins, including the highly conserved E protein, as well as 3a, ORF7b and ORF10 proteins, suggesting an exceptionally high importance of viroporin functions in the Coronavirus life cycle [16–18].

The results obtained here indicate that BIT225 is an inhibitor of SARS-CoV-2 E protein ion channel activity.

https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1011328