New strategies to block Henipavirus infection – Henipastop

The Hendra and Nipah viruses (HeV and NiV) belong to the Henipavirus genus within the Paramyxoviridae family. These zoonotic viruses have been recently recognized as human pathogens responsible for deadly encephalitis. HeV infection is a serious threat to horse livestock in Australia, with sporadic and lethal transmission to humans having also been observed. After the first cases of human infection in 1998 in Malaysia, NiV has regularly reemerged since 2001 (2011 included) in Bangladesh, with a case fatality rate approaching 75%. Asymptomatic infection in up to 60% of exposed people may also lead to late-onset disease or relapse of encephalitis years after initial infection, as well as persistent neurological sequelae. Cases of inter-human transmission of NiV further extend its potential to cause deadly outbreaks. Furthermore, the endemic area of henipaviruses extends outside Australia and Asia. The susceptibility of humans, the wide host range and interspecies transmission led to the classification of HeV and NiV as biosecurity level 4 (BSL-4) pathogens. To date neither therapeutic agents nor vaccines are available to fight against these severe pathogens. The prevention and/or containment of present and future outbreaks will depend on our ability to design efficient strategies to fight against these novel viruses. The goal of our project is to develop candidate drugs efficient against henipaviruses. To this endeavor, we will focus on three aspects, namely (i) the investigation of heparin and derivatives as inhibitors of NiV attachment to non-permissive host cells able to mediate transinfection and dissemination in the organism, (ii) the assessment and improvement of peptides able to inhibit NiV-mediated cell-cell fusion and virus entry to protect and/or cure animals against Henipavirus infection and (iii) the search of chemical libraries for small compounds able to block protein-protein interactions (PPIs) crucial for Henipavirus transcription and replication.
The strength of the project resides in the combination of three different antiviral strategies, each possessing distinctive advantages in terms of either preliminary encouraging results (inhibition of attachment and of fusion) or of originality and high potential for discovering new antiviral compounds (inhibition of PPIs crucial for transcription and replication). To achieve these goals, four teams will join their complementary skills and expertise in a project that will combine both in vitro and in vivo studies. The consortium consists in a balanced set of complementary expertise. Partners 1 and 2 have a strong background in the molecular characterization (Partner 1) and infection (Partner 2) of paramyxoviruses (and in particular of Nipah and the related measles virus). Partner 3 brings state of the art technology for the study of glycosaminoglycans (a family of polysaccharides including heparin) and Partner 4 will provide the necessary well trained BSL-4 team for the use of Jean Mérieux-INSERM BSL-4 laboratory (Lyon) and cutting-edge facilities for studying dangerous human pathogens in a fully safe and confined environment. In addition, Partner 1 is one of the worldwide leading experts in the field of PPIs mediated by intrinsically disordered regions, such as those targeted in the present project, and also benefits from the implementation in her lab of an IBISA platform for antiviral screening and of a medicinal chemistry team.