Project

Back to overview

Paramyxovirus cell exit: from basics to drug discovery strategies

English title Paramyxovirus cell exit: from basics to drug discovery strategies
Applicant Plattet Philippe
Number 173185
Funding scheme Project funding (Div. I-III)
Research institution Abteilung für Klinische Forschung Dept. für klinische Veterinärmedizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Medical Microbiology
Start/End 01.05.2017 - 31.10.2021
Approved amount 800'818.00
Show all

All Disciplines (3)

Discipline
Medical Microbiology
Pharmacology, Pharmacy
Structural Research

Keywords (6)

Cell exit-based bioassays; Antiviral drug strategies; Cell exit mechansims; Paramyxovirus; M interactome; Matrix protein

Lay Summary (French)

Lead
Malgré l’accès à des technologies modernes d’identification de nouveaux antiviraux (à base de structure 3D ou par criblage à haut débit), il n’existe pas encore d’inhibiteurs efficaces contre la grande majorité des maladies infectieuses. Par ailleurs, comme les polymérases des virus à ARN induisent un haut taux d’erreurs lors de la réplication, des résistances contre des molécules inhibitrices émergent très rapidement. Ainsi, la mise en place de tests biologiques innovants ciblant spécifiquement des étapes précises du cycle viral devrait permettre l’identification et le développement de nouvelles classes d’antiviraux. Une telle approche a le potentiel de pouvoir créer de nouvelles thérapies combinées pour le traitement de maladies infectieuses dangereuses.
Lay summary

La famille des virus Paramyxoviridae comprend un grand nombre de virus qui peuvent avoir des effets critiques sur la santé humaine et animale. Parmi ceux-ci, se trouve le virus de la rougeole qui continue de tuer plus de 100’000 personnes par année, malgré le fait qu’un vaccin très efficace soit disponible. En parallèle, le virus de la maladie de Carré (Canine Distemper Virus; CDV), la version animale du virus de la rougeole, possède la caractéristique unique d’infecter non seulement les chiens, mais aussi un nombre toujours plus important d’animaux carnivores. Récemment, il a été démontré que CDV a évolué et infecte maintenant de nouvelles espèces telles que le singe, des épidémies très sévères ayant été signalées. Ces épidémies confirment la capacité inquiétante de CDV à acquérir rapidement les modifications moléculaires nécessaires à l’infection de nouvelles espèces, devenant une menace potentielle pour la santé humaine. Ainsi, le projet proposé s’articule tout d’abord autour de la compréhension de la sortie du virus de la rougeole et de CDV des cellules hôtes puis, dans un deuxième temps, autour de la production de tests innovateurs permettant l’identification de nouvelles classes d’antiviraux.

Au-delà du potentiel d’améliorer et de protéger de manière significative la santé humaine et animale, nous pensons que de tels inhibiteurs pourraient également jouer un rôle essentiel dans la campagne mondiale visant à éradiquer le virus de la rougeole de la planète. En effet, malgré l’efficacité excellente du vaccin et le travail remarquable des services de santé humaine, le seuil fatidique de 95% de couverture vaccinale, qui mènerait à une éradication complète du virus de la rougeole, n’est toujours pas atteint. Par conséquent, l’approche qui consisterait à combiner la vaccination avec des traitements antiviraux pourrait se révéler cruciale pour atteindre l’objectif de l’OMS, à savoir l’éradication globale du virus de la rougeole.

Direct link to Lay Summary Last update: 12.04.2017

Responsible applicant and co-applicants

Employees

Project partner

Publications

Publication
Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor
Kalbermatter David, Shrestha Neeta, Ader-Ebert Nadine, Herren Michael, Moll Pascal, Plemper Richard K., Altmann Karl-Heinz, Langedijk Johannes P., Gall Flavio, Lindenmann Urs, Riedl Rainer, Fotiadis Dimitrios, Plattet Philippe (2019), Primary resistance mechanism of the canine distemper virus fusion protein against a small-molecule membrane fusion inhibitor, in Virus Research, 259, 28-37.
Regulatory Role of the Morbillivirus Attachment Protein Head-to-Stalk Linker Module in Membrane Fusion Triggering
Herren Michael, Shrestha Neeta, Wyss Marianne, Zurbriggen Andreas, Plattet Philippe (2018), Regulatory Role of the Morbillivirus Attachment Protein Head-to-Stalk Linker Module in Membrane Fusion Triggering, in Journal of Virology, 92(18), 1-20.
Dimerization efficiency of canine distemper virus matrix protein regulates membrane-budding activity
Bringolf Fanny, Bringolf Fanny, Herren Michael, Herren Michael, Wyss Marianne, Vidondo Beatriz, Langedijk Johannes P., Zurbriggen Andreas, Plattet Philippe (2017), Dimerization efficiency of canine distemper virus matrix protein regulates membrane-budding activity, in Journal of Virology, 91(16), e00521-17- e00521-17.

Associated projects

Number Title Start Funding scheme
153281 Unraveling Paramyxovirus Cell Entry 01.05.2014 Project funding (Div. I-III)

Abstract

The Paramyxovirus family encompasses enveloped, negative-stranded RNA viruses, which include, among others, major pathogens such as respiratory syncytial virus (RSV), measles virus (MeV), canine distemper virus (CDV) or henipaviruses (Nipah virus [NiV] and Hendra virus [HeV]). While RSV causes acute lower respiratory tract infections in infants/young children worldwide and is associated with approximately 3 million hospitalizations per year, MeV still kills more than 100.000 people per year and CDV induces devastating epidemics in wild animals, including endangered species. In addition, henipaviruses are classified as biosafety level 4 agents, infecting both animals and humans with high mortality rates. However, despite few promising candidates, lack of basic understanding of many aspect of the paramyxovirus’ life cycle still precludes the rationale design of antiviral drugs. On the other hand, structure-based drug design and high throughput screenings (HTS) are powerful technologies in modern drug discovery. However, while X-ray crystallography remains technically very challenging, HTS combined with recombinant live-virus-based readouts may identify hits often trapped to block cell-entry and/or replication stages. In addition, the paramyxoviruses’ polymerase features a high mutational rate, which in turn allows for the swift generation of drug-resistant pathogenic variants. Identifying drugs targeting the viral cell-exit stage therefore represents an additional, but under-exploited, alternative for the development of new classes of inhibitors and reach highly desired combined therapy protocols.Hence, in this research proposal, my aim is to fill this gap by unraveling the mechanics of the paramyxovirus cell-exit process (MeV, CDV and NiV) and to employ this knowledge to engineer innovative and highly-sensitive targeted “cell-exit bioassays”. Such assays will be designed to match HTS requirements and potentially initiate drug discovery campaigns. To achieve these ambitious aims, a two-pronged approach will be conducted.Part 1: I plan to unravel the molecular mechanisms of the paramyxovirus cell-exit process by focusing the research on the viral matrix protein (M), which, at least in part, orchestrates viral assembly and budding. Specifically, structure-based mutagenesis combined with newly designed biochemical and functional assays will be used to investigate the M-oligomerization propensity and derived putative specific bioactivities. To facilitate this aim, anti-M nanobodies (Nbs) will be generated. Indeed, the unmatched biophysical features of Nbs make them ideal molecular tools in basic and applied research (i.e. potentially binding to epitopes inaccessible to traditional antibodies, suitable for intracellular expression, exhibiting good oral delivery profiles). Finally, the novel biotin identification (“BioID”) technology will be applied to identify new M-binding partners. This may reveal yet unknown cellular pathways that must be hijacked by M to set the conditions for efficient viral replication, assembly and exit. Part 2: I then plan to use the knowledge gained in Part 1 to engineer/improve targeted “cell-exit bioassays” matching with HTS protocols. VLP- and full particle-based assays will be engineered by combining synthetic biology with the novel Nano-luciferase (and derived split) reporter system, as well as with an innovative drug-dependent protein expression-control technology (“SMASh”). This may define simple, robust and highly-sensitive bioassays.Overall, I am confident that this dual approach has the potential to synergize and set the stage to initiate, in a near future, drug discovery campaigns for the identification of desired “cell-exit” inhibitors. Such antivirals, combined with entry and replication inhibitors, may offer realistic options to fight these pathogenic envelope RNA viruses.
-