![]() ![]() (Employee) Xiao-Jian Zhou, PhD, Atea Pharmaceuticals, Inc. (Employee) Adel Moussa, PhD, Atea Pharmaceuticals, Inc. Preclinical safety studies are in progress and clinical trials will be initiated thereafter. The potent activity of AT-281 against Dengue virus in vitro and the efficacy of its salt form, AT-752, in the terminal AG129 mouse model warrant further clinical development of the drug. Panel a: health score: 1, healthy 2, coat slightly ruffled 3, coat ruffled/wet 4, coat very ruffled, eyes slightly closed/inset 5, coat very ruffled, eyes closed/inset 6, coat very ruffled, eyes closed/inset, moribund requiring humane euthanasia 7, found dead. Efficacy of AT-752 in the AG129 mouse model of Dengue infection. Antiviral Activity of AT-281 Against Various Flaviviruses in Huh-7 Cell Culturesįigure 1. In contrast, AT-752 treated mice survived up to day 19, eventually succumbing to model-induced CNS sequelae. Serum and spleen viral loads in control mice declined between days 4 and 8 but no control mice survived beyond day 8. Oral administration of AT-752 to Dengue-infected AG129 mice substantially improved survival, prevented weight loss and lowered viral loads by day 6, with virus being undetectable on day 8 and thereafter (Figure 1). No toxicity was observed up to the highest concentrations tested (172 µM). In vitro EC90 values for AT-281 against Dengue, West Nile and Yellow Fever viruses ranged from 0.26 to 0.64 µM and EC50 values for Zika and Japanese encephalitis were 0.21 and 0.64 µM, respectively (Table 1). AT-281 efficacy was evaluated based on overall health score, survival, weight loss and viral load in serum and spleen. with serum and spleen viral RNA levels determined by plaque assay. Six groups each (n=5) of treated and control mice were scheduled to be sacrificed on days 4, 6, 7, 8, 10 and 21 p.i. doses (500 mg/kg) for 7 days starting 1 h post-inoculation (p.i.). inoculation with Dengue virus type 2 (strain D2Y98P, 1x105 virus particles) followed by b.i.d. AG129 (α-, β- and γ-interferon knock-out) mice received an oral dose of AT-752 (1000 mg/kg) 4 h before s.c. Effective concentrations of AT-281 required to inhibit virus yield reduction by 90% (EC90) and to prevent cytopathic effect by 50% (EC50) were determined, respectively, by visual examination and by neutral red staining, as was cytotoxicity. Here we report the potent in vitro activity of AT-281, the free base form of AT-752, against Dengue virus and other flaviviruses and the in vivo efficacy of AT-752 in a mouse model of Dengue viral disease.Īntiviral activities of serial dilutions of AT-281 were evaluated in infected Huh-7 cells. The increasing global prevalence of human Dengue virus infection and the potential for life-threatening sequelae highlight the significance of this unmet medical need. ![]() LY411575, a gamma secretase inhibitor, exhibited an IC50 of 72nM and reduced percent infection to levels indistinguishable from the mock infection control. We identified four concentration-dependent inhibitors of DENV with nanomolar potencies including: Nexium, Pralatrexate, GW4064, and LY411575. We then developed a single-cell infection classifier for antiviral efficacy and performed high-throughput drug screening of 960 compounds. Using high-content screening, we quantified the morphological patterns of NS4B and envelope (E) protein expression versus time and developed a viral pseudotime model that was able to predict the infection progression to enable drug screening. Drug-repurposing and high-content screening were leveraged to efficiently identify antivirals likely to inhibit NS4B. Antivirals that target NS4B, the replication compartment forming protein of DENV and the flavivirus family, are a promising new drug class that minimize cytotoxic effects to host cells. Thus, there is an urgent need to identify dengue virus antivirals. Additionally, the available vaccine for DENV can increase the risk of severe dengue fever for those who have never had a DENV infection due to antibody-dependent enhancements. Dengue Virus (DENV) causes dengue fever, a pandemic-potential disease with currently no FDA-approved antivirals.
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