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This article provides recommendations for the design and conduct of early-phase clinical trials for dengue therapeutics. The focus is on antiviral therapies, as they are the main area of drug development for dengue. The article discusses patient populations, diagnosis, safety signals, clinical and laboratory endpoints, virological endpoints, dosing and pharmacology, non-invasive physiological monitoring, and sample sizes for early-phase studies. The article acknowledges the challenges in developing therapies for dengue but provides a standardized reporting approach to accelerate clinical testing. [Extracted from the article]

Highlights: [•] No vaccine or antiviral drug is currently available for dengue virus (DENV) infection. [•] We review strategies for dengue drug discovery. [•] We review successes and challenges in dengue drug discovery. [•] Knowledge acquired in the past decade provides a better rationale for ongoing dengue drug discovery. [Copyright &y& Elsevier]

Abstract: Dengue virus (DENV) is a mosquito-borne flavivirus responsible for 50–100 million human infections each year. The development of DENV chemotherapy requires high-throughput screening (HTS) assays. A dengue virus-like particle (VLP) has been constructed using viral structural proteins to package a Renilla luciferase reporter replicon. VLP could be produced by either the sequential electroporation of the replicon RNAs and the structural gene RNAs or by electroporating replicon RNA into a stable cell line expressing the structural proteins. In both approaches, the key to produce high titer VLP (3×106 foci-forming unit/ml) is to use low temperature (30°C) in the packaging step. In addition, exogenous expression of host protease furin increased VLP infectivity. The infection could be blocked by antibodies against viral envelope protein and by an inhibitor of viral NS5 polymerase, but not by an inhibitor of host alpha-glucosidase (castanospermine). The VLP infection assay was optimized for HTS in a 384-well format with consistent and robust signal, providing a simple and rapid cell-based assay for screening inhibitors against DENV entry, translation, and replication in an HTS format. [Copyright &y& Elsevier]