A previously unknown druggable pocket formed by viral proteins VP1 and VP3 in enteroviruses and rhinoviruses has bee identified in new research. The finding may allow development of new antiviral medications for the common cold, polio, and other illnesses, according to the study by Rana Abdelnabi and Johan Neyts of the University of Leuven, Belgium, and James Geraets and Sarah Butcher of the University of Helsinki and their colleagues.
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 such as 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.
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.
They 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.
[caption id=“attachment_98951” align=“aligncenter” width=“680”] (A) The atomic model of CVB3 Nancy in complex with compound 17 based on the cryo-EM density shows the position of the drug at an interprotomer site, located between adjacent VP1 chains (gray and blue) and VP3 (red).
B) Difference density for compound 17 (mesh), with an atomic model of compound 17 fitted in, shown at 1.5 standard deviations above the mean.
(C) The process of difference mapping: simulated density map was generated from 1COV for the capsid proteins (here colored blue, light blue, red by protein) and normalized to the cryo-EM density map in UCSF Chimera. When the simulated density map of 1COV was then subtracted from the cryo-EM density, the difference density remained (orange).
(D) Model docked into map.
(E) Electrostatic analysis of the surface pocket. The raw cryoelectron microscopy data are deposited in the EMPIAR (Electron Microscopy Public Image Archive) database with the ID: EMPIAR-10199. CVB, Coxsackievirus B; EM, electron microscopy; UCSF, University California San Francisco.
Credit: Abdelnabi R, st al CC-BY[/caption]
Although picornaviruses have been studied for decades, the authors discovered a previously unknown 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 variants of the antiviral molecule to maximize the activity against a broad range of picornaviruses.
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 be less viable, making the drug relatively “resistance-proof.”
Further work to develop these compounds into effective drugs is ongoing.
“These results open up a new avenue for the design of broad-spectrum antivirals against rhinoviruses and enteroviruses, both of which are major human pathogens,"
Abdelnabi R, Geraets JA, Ma Y, Mirabelli C, Flatt JW, Domanska A, et al. A novel druggable interprotomer pocket in the capsid of rhino- and enteroviruses PLoS Biol 17(6): e3000281. https://doi.org/10.1371/journal.pbio.3000281
Top Image: James Geraets