How to stop viruses at the doorstep
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CeMM Adjunct PI Thijn Brummelkamp and his team discovered a surprising role of a host enzyme in Picornavirus life cycle. Their study, published in Nature, offers a completely new approach for antiviral therapies, which are soon anticipated to enter preclinical development.
Polio, hepatitis A, but also the common cold – Picornaviruses cause a broad range of human diseases. Their structural and genetic diversity made it difficult to develop effective antiviral therapies against this large family of viruses. Lacking the membrane envelope present in other types of viruses, Picornaviruses have developed a sophisticated – and largely unknown – mechanism to safely deliver their RNA packaged into protein shells called capsids into the cytoplasm of their host cells.
In this crucial step of Picornavirus infection, CeMM Adjunct Faculty Member Thijn Brummelkamp, group leader at CeMM’s EU-Life partner institute NKI, and his team identified a hitherto unknown and surprising role of a protein called PLA2G16: Located at the host’s cell membranes, PLA2G16 is essential for poliovirus entry, acting at a previously unknown step between pore formation and translation of viral RNA (published in Nature, doi:10.1038/nature21032).
The scientists didn´t leave it with that: Cells in which the PLA2G16 gene was deleted were resistant to virus infection, and mice lacking the gene were protected from a dose of a virus that would normally be lethal. Inhibition of the drugable PLA2G16 Protein surrenders picornavirus particles to a clearance mechanism normally associated with bacterial infections.
“These findings suggest that PLA2G16 can be exploited as novel antiviral target for diseases caused by picornaviruses. Furthermore, as such drugs would target a host factor rather than a viral protein, there would be a high barrier for the virus to develop drug resistance”, explains Dr Thijn Brummelkamp.
The CeMM spin-off company Haplogen, of which three CeMM faculty members were scientific founders, is developing drugs targeting PLA2G16 in partnership with Evotec which are anticipated to enter pre-clinical development in the course of 2017.
Publication:
Jacqueline Staring, Eleonore von Castelmur, Vincent A. Blomen, Lisa G. van den Hengel, Markus Brockmann, Jim Baggen, Hendrik Jan Thibaut, Joppe Nieuwenhuis, Hans Janssen, Frank J. M. van Kuppeveld, Anastassis Perrakis, Jan E. Carette & Thijn R. Brummelkamp. PLA2G16 represents a switch between entry and clearance of Picornaviridae. Nature, Jan 2016. DOI: 10.1038/nature21032.
Funding:
This work was partially funded by the Swiss National Science Foundation (SNF), the Cancer Genomics Center (CGC), the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NOW) and the European Research Council (ERC).