| Autor: |
Juho Hokkanen, Maxi Heyner, Juana Díez, Valtteri Rinne, Mark Brönstrup, Kirsten Harmrolfs, Yuichi Sugiyama, Katharina Rox, Rolf Müller, Andrea Kröger, Jana Krull, Gemma Perez Vilaro |
| Rok vydání: |
2021 |
| Předmět: |
|
| Zdroj: |
ACS Pharmacol Transl Sci |
| ISSN: |
2575-9108 |
| DOI: |
10.1021/acsptsci.1c00078 |
| Popis: |
[Image: see text] While a drug treatment is unavailable, the global incidence of Dengue virus (DENV) infections and its associated severe manifestations continues to rise. We report the construction of the first physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model that predicts viremia levels in relevant target organs based on preclinical data with the broad spectrum antiviral soraphen A (SorA), an inhibitor of the host cell target acetyl-CoA-carboxylase. SorA was highly effective against DENV in vitro (EC(50) = 4.7 nM) and showed in vivo efficacy by inducing a significant reduction of viral load in the spleen and liver of IFNAR(–/–) mice infected with DENV-2. PBPK/PD predictions for SorA matched well with the experimental infection data. Transfer to a human PBPK/PD model for DENV to mimic a clinical scenario predicted a reduction in viremia by more than one log(10) unit for an intravenous infusion regimen of SorA. The PBPK/PD model is applicable to any DENV drug lead and, thus, represents a valuable tool to accelerate and facilitate DENV drug discovery and development. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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