Picornaviruses include rhinoviruses and enteroviruses. Rhinoviruses cause millions of cases of upper respiratory infections, “colds”, yearly and contribute to asthma, and enteroviruses are responsible for millions of infections including cases of meningitis, encephalitis and polio. There are currently no antivirals that can be used for the treatment or prevention of any of the rhino- or enteroviruses.
"For 30 years, antiviral research on this huge group of human pathogenic viruses has focussed on the initial observations by Michael Rossman and colleagues that one site is druggable, and despite many trials, we still have no drug on the market to cure infection. This study shows that we have another druggable site which we found to be a mechanistic weakness of the virus that we can exploit", says Professor Sarah Butcher from the Institute of Biotechnology, Helsinki Institute of Life Sciences, University of Helsinki.
To replicate, viruses must interact with host cells, and in doing so, often need to change shape; stabilizing the virus particle is therefore thought to be a promising strategy for preventing replication. In a search for potential antiviral candidates, the authors found a compound that stabilized a model picornavirus, and performed cryo-electron microscopy (cryo-EM) of the drug-virus complex to determine how the drug exerted its effect. Cryo-EM involves combining thousands of two-dimensional images to develop a highly detailed three-dimensional image of the target.
Although picornaviruses have been studied for decades, the authors discovered a previously unknown pocket, or indentation, on the surface of the virus, in which the compound had lodged, thereby stabilizing it against the kind of shape change that would allow interaction with host cells. The team then used the compound as a starting point to generate multiple compound variants to maximize the antiviral activity against a broad range of picornaviruses.
What may be the limitations found by researchers? A major challenge in developing antiviral medications is that viruses mutate quickly, changing in ways that make a once-useful drug ineffective. While it is possible that the newly-discovered pocket may also mutate to make picornaviruses resistant to therapies developed against them, the authors suggest the pocket may be crucial enough for viral replication that viruses containing mutant versions may not be viable, making the drug relatively “resistance-proof.”
“The limitations are that although this region is present in the viruses that we have so far looked at, molecules will need to be tailored to specific virus types. We also showed that the virus can mutate to escape the drug, but this normally made the resulting virus less fit. These are early days, and much work needs to be done before we will have a cure in the pharmacy. This could be a good drug to use in combination with molecules targeting different parts of the viral replication, as RNA viruses are so rapidly able to mutate and a multipronged attack will be more effective than just one molecule alone”, says Butcher.
The study also contributes to our wider understanding of this area of viruses. According to Butcher it reminds us that in such complex systems as a viral capsid we can upset the equilibrium required for infection by subtle addition of simple molecule that can act as molecular glue.
Original article:
A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses
Rana Abdelnabi , James A. Geraets , Yipeng Ma , Carmen Mirabelli , Justin W. Flatt, Aušra Domanska, Leen Delang, Dirk Jochmans, Timiri Ajay Kumar, Venkatesan Jayaprakash, Barij Nayan Sinha, Pieter Leyssen, Sarah J. Butcher , Johan Neyts. PLOS Biology. Published: June 11, 2019
Funding:
This work was funded by the BELVIR project from BELSPO (IUAP), People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme FP7/2007-2013/ under REA grant agreement n°612308 AIROPico (to SJB and JN), a postdoctoral mandate Internal Fund from KU Leuven (PDM/17/178 to RA), a Fellowship from China Scholarship Council (CSC) (Grant n°. 201406040056; to YM), Academy of Finland (275199 to SJB) and Sigrid Juselius Foundation (to SJB). Microscopy was carried out with the support of the Biocenter Finland National Cryo-EM Unit, Instruct-FI and n°653706 iNEXT (proposal n°1973).
Video:
Movie showing the structure of coxsackievirus B3 zooming into show how a small molecule (in purple) binds to the capsid. Movie distributed under creative commons license 3.0. By Abdelnabi, Geraetset al.
See also:
- Molecular and Integrative Biosciences Research Program
- Doctoral Programme in Microbiology and Biotechnology
Contacts:
Johan Neyts of the University of Leuven, Belgium, johan.neyts@kuleuven.be