Fosaprepitant Dimeglumine Alleviates Dengue Virus Infection and Virus-Induced Inflammatory Responses.

Abstract

Dengue remains one of the most important mosquito-borne diseases. Currently, in the absence of targeted antiviral therapy, the treatment of dengue remains supportive. In this study, we found that the neurokinin-1 receptor antagonist fosaprepitant dimeglumine, an FDA-approved drug for the prevention of nausea and vomiting, efficiently inhibited dengue virus (DENV) infection in vitro. Fosaprepitant dimeglumine dose-dependently inhibited DENV replication in several cell lines, including A549 cells and THP-1-derived macrophages, with IC₅₀ values of 3.26 and 4.20 μM, respectively. The time-of-drug-addition and time-of-drug-elimination assays revealed that fosaprepitant dimeglumine acted at late stages after virus entry. Fosaprepitant dimeglumine efficiently inhibited DENV genome replication in a stable reporter DENV-3 replicon cell line. The immune-mediated cytokine storm is known to play a key role in the severe manifestation of dengue. The interferon γ-inducible protein 10 (IP-10) and IL-6 are upregulated in severe dengue. For the first time, we report that fosaprepitant dimeglumine significantly suppressed the levels of the proinflammatory cytokines IL-6 and IP-10 in differentiated THP-1 macrophages infected with DENV-2. Fosaprepitant dimeglumine not only effectively inhibits DENV replication but also attenuates virus-induced inflammatory responses, which makes it a promising candidate for drug repurposing in the treatment of severe dengue.