Immunostimulating molecules with a broad-spectrum antiviral activity: a proof of concept in non-human primate models – STING-2.0

Our therapeutic arsenal to treat virus-infected patients is extremely limited, and there is a critical need for broad-spectrum antiviral molecules that could be used against multiple viruses. Among possible strategies, the idea of molecules stimulating the innate immune response in host cells is of growing interest.
Based on this strategy, our research group at Institut Pasteur (CNRS URA3015) has developed a high-throughput functional assay to monitor the activation of antiviral genes in human cells (US patent N°12/648225; “A mammalian cell-based screening assay to identify antiviral compounds that stimulates interferon-target genes”). A total of 40.000 molecules from different chemical compound libraries have been screened with this system, and two were selected for their ability to stimulate the antiviral immune response in human cells. These two molecules were subsequently shown to abrogate the in vitro infection of human cells by numerous viruses including pathogenic arboviruses (dengue virus, west-nile virus, and chikungunya virus) and respiratory viruses (human respiratory syncytial virus, measles virus, human parainfluenza virus 3, coronavirus 229E) for which there is no treatment available. Most importantly, these molecules showed virtually no adverse effects in vitro, and thus represent promising lead molecules for the development of a broad-spectrum antiviral drug (European Patent N°10/290426; “Novel derivatives useful as antiviral agents”).
In collaboration with chemists from CNRS at Institut Curie, the activity of these molecules has been significantly improved by the introduction of subtle modifications, and their IC50 now equals 500 nM. We will pursue this effort to identify even more active molecules but in the same time, a proof of concept of their antiviral activity in vivo must be established. Since our two lead molecules are only active in primate cells, this prevents the use of small animal models like mice for in vivo studies.
In this proposal, we present a project to test our lead molecule in Cynomolgus monkeys (Macaca fascicularis) in collaboration with Cynbiose (Lyon), a small company specialised in pre-clinical assays in non-human primate models. Our aim will be to demonstrate in vivo the antiviral activity of our lead molecules on chikungunya virus (CHIKV) and measles virus (MV), two human viruses that are infectious in monkeys and represent prototypes for arbovirus and respiratory virus infections, respectively.