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Biology subjects

Bobardt, M.

Publications and source records attributed to Bobardt, M..

2 recordsLinked to original sources
bioRxiv2023

The Cyclophilin Inhibitor Rencofilstat Decreases HCV-induced Hepatocellular Carcinoma Independently of Its Antiviral Activity

There is an urgent need for the identification of new drugs that inhibit HCV-induced hepatocellular carcinoma (HCC). Our work demonstrates that cyclophilin inhibitors (CypI) represent such new drugs. We demonstrated that the non-immunosuppressive cyclosporine A (CsA) analog (CsAa) rencofilstat possesses dual therapeutic activities for the treatment of HCV infection and HCV-induced HCC. Specifically, we showed that HCV infection of humanized mice results in the progressive development of HCC. This was true for four genotypes tested (1 to 4). Remarkably, we demonstrated that rencofilstat inhibits the development of HCV-induced HCC in mice even when added 16 weeks post-infection when HCC is well established. Importantly, we showed that rencofilstat drastically reduces HCC progression independently of its anti-HCV activity. Indeed, the CypI rencofilstat inhibits HCC while other anti-HCV agents such as NS5A (NS5Ai) and NS5B (NS5Bi) fail to reduce HCC. In conclusion, this study shows for the first time that the CypI rencofilstat represents a potent therapeutic agent for the treatment of HCV-induced HCC.

microbiology↗
bioRxiv2023

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

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 calcium-induced ion channel activity or TMEM16A in Xenopus oocytes. BIT225 administered by oral gavage for 12 days starting 12 h 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 h 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. AUTHORS SUMMARYAntiviral agents are highly important for the management of COVID-19. We need new antivirals, because available drugs have major drawbacks that limit their use and are threatened by drug resistance. This study demonstrates that the small molecule drug BIT225 is an inhibitor of an important viral ion channel (E-protein). E-protein is required for virus replication and is involved in eliciting inflammatory response to infection. Exacerbated inflammation is a hallmark of severe COVID-19 in mice and in humans. In a mouse model of severe SARS-CoV-2 infection, BIT225 treatment starting before or 24 hours after infection could protect all treated mice from developing disease, from experiencing weight loss and from death (100%, n=17), while all untreated mice developed severe disease, started to lose body weight from day 3 onwards and died within 9 days after infection. BIT225 treatment was associated with potent suppression of virus load, and reduced inflammation markers, consistent with effective clearance of the virus. These results are remarkable for the exceptionally high efficacy achieved with a new mechanism of action. BIT225 is a clinical stage drug candidate with an established human safety profile. These results support clinical evaluation of BIT225 for the treatment of human SARS-CoV-2 infection.

molecular biology↗