In 2012, a novel human coronavirus (MERS-CoV) was identified in the Middle East as the causative agent of a severe acute and/or fatal respiratory syndrome. Since its identification, it has been responsible for 211 laboratory-confirmed cases including 88 deaths. Most cases are sporadic but human-to-human transmission has been documented both in hospital settings and community clusters. Emergence of this new coronavirus in humans raises concerns about a possible widespread outbreak, similar to the one previously caused by SARS-CoV in 2003. Control of such emerging viral pathogens constitutes a major public health issue. However, despite the urgent need for efficient and safe therapeutics, there is currently no antiviral treatment nor vaccine available as yet and there is no evidence that they may become available nor when. Innovative strategies are thus required to fight against these emerging hazardous coronaviruses adequately. In this context, the main objective of the CoV-SigN project is to identify innovative efficient antiviral compounds against MERS-CoV and SARS-CoV that target the host cell instead of viral molecular determinants. Based on the postulate that gene expression profiling can be considered as a global “fingerprint” of the disease/drug effect, this innovative strategy was already successfully achieved by the coordinator partner with seasonal influenza A viruses. This proof-of-concept led to an ongoing clinical trial that evaluate a marketed drug for new antiviral indication. In term of experimental strategy, the CoV-SigN project aims to identify in vitro and in vivo host transcriptomic signatures associated with viral infections, followed by the in silico screening of large databases for existing compounds that can counteract these viral signatures. Next, candidates will be evaluated by using in vitro cellular assays for their expected antiviral properties against MERS-CoV and SARS-CoV. Sample from the two patients collected in hospital settings (CHRU Lille), will constitute a pivotal added value to the project by comparison with the initial proof-of-concept pilot study. By bringing additional physiological data (such as immune and inflammatory responses, different steps of pathology progression), in vivo signatures of infections will add more biological relevance to the project by implementing in vitro signatures analysis and strengthening the selection of candidate compounds to test for their antiviral property. Use of such new antivirals should considerably decrease the risk of emergence of drug resistance and would be well adapted for short treatment duration and therefore should not impact cellular functions permanently. Thus, the CoV-SigN project constitutes an ideal approach to characterize inhibitors particularly adapted to target acute respiratory pathogenesis demonstrated by MERS-CoV and SARS-CoV viruses. This project is part of a drug-repurposing concept and could provide important financial and regulatory advantages compared to the time-consuming and expensive development of de novo antiviral molecules. The strength of the proposal relies on the complementary and synergistic fundamental, technological, translational and clinical expertise of the four partners. Moreover, the combination of pre-existing collaborations between partners, established proof-of concept and preliminary experimental setup/results from patients’ samples will constitute key parameters for the successful achievement of the CoV-SigN project in terms of scientific output and medical applied perspectives.