Discovery of (pan)-henipavirus antivirals using novel in vitro and in vivo Cedar virus models
Henipaviruses are negative-strand RNA viruses in the Paramyxoviridae family with currently five species: Cedar, Ghanaian bat, Hendra, Mojang and Nipah henipaviruses. They are naturally harbored by pteropid fruit bats (flying foxes) and microbats of several species found throughout the tropics and subtropics. Henipavirus outbreaks in humans have occurred in northern Australia and Southeast Asia since the mid-1990s. Hendra virus (HeV) has been reported nearly annually since 1994 in the eastern states of Australia, while Nipah virus (NiV) outbreaks in humans were first reported in 1998-99 in Malaysia and Singapore and are reported almost annually in India and Bangladesh. The broad geographical distribution of the henipavirus natural animal reservoir, the high overall NiV and HeV case fatality rate in humans as well as the growing evidence of multiple routes of virus transmission, including human-to-human transmission, are causes of serious concern for henipaviruses to become epidemic or pandemic, and have turned NiV and HeV viruses into high priority pathogens of the World Health Organization (WHO). Despite the recognized high epidemic and pandemic potential of henipaviruses, no safe and effective vaccines nor therapeutics are currently available for human use. This PhD project addresses this need and aims to discover novel small molecule antivirals directly acting against henipaviruses and preferably with pan-paramyxovirus activity. To this end, the PhD project has the following aims: 1. Set up and perform a high throughput phenotypic screening assay with Cedar virus (CedV), a non-pathogenic henipavirus that can serve as a surrogate for BSL-4 NiV/HeV. 2. Confirm and validate henipavirus antiviral activity of hit compounds in multiple complementary assays. In addition, compounds will be assessed for activity against HeV and NiV by partner institutes and for broader-spectrum anti-paramyxovirus activity. In parallel, they will be used to isolate virus variants that show phenotypic resistance to the respective compounds in a first step to unravel their precise molecular mechanism of action. 3. Establish the first CedV infection model in mice or hamster to allow future evaluation of the efficacy of small molecules in vivo.