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Title: Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses}
Article:
Abstract:
The replication of enterovirus 71( EV71) and coxsackievirus A16( CVA16), which are the major cause of hand, foot and mouth disease( HFMD) in children, can be inhibited by the capsid binder GPP3. Here, we present the crystal structure of CVA16 in complex with GPP3, which clarifies the role of the key residues involved in interactions with the inhibitor. Based on this model, in silico docking was performed to investigate the interactions with the two next-generation capsid binders NLD and ALD, which we show to be potent inhibitors of a panel of enteroviruses with potentially interesting pharmacological properties. A meta-analysis was performed using the available structural information to obtain a deeper insight into those structural features required for capsid binders to interact effectively and also those that confer broad-spectrum anti-enterovirus activity.
Introduction:
HFMD is caused by enterovirus infections, predominantly CVA16 and EV71[1, 2]. This childhood infection is usually mild, but occasionally leads to neurological disease and even death in the most extreme cases. Major outbreaks have been reported in the past, predominantly in Asia, leading to these viruses becoming a growing public health concern. Currently, there is no vaccine or effective drug available for the treatment of these infections[3]. Enteroviruses belong to the Picornaviridae family of small viruses with a single-stranded, positive-sense genomic RNA. The viral genome is enclosed in a non-enveloped icosahedral capsid that is built out of 60 copies of the structural proteins VP1 to VP4. VP1 surrounds the 5-fold axes and VP2 and VP3 alternate around the 2- and 3-fold axes, while VP4 forms part of the inner lining of the capsid. Canyon-like depressions encircle the 5-fold axes and are frequently the sites for receptor attachment[4]( Fig 1a). Uncoating, the process during which the capsid opens up to release the viral genome into the host-cell cytosol to initiate virus replication, is key to enterovirus infection. Structural analysis has revealed that each of the 60 VP1 proteins in the enterovirus capsid contain a hydrophobic ‘pocket factor’. This is a natural lipid( for instance sphingosine), which is buried in a hydrophobic pocket at the base of the canyon, within the VP1 capsid protein( Fig 1a). Expulsion of this molecule during binding of the virus to its receptor prepares the particle for a cascade of structural rearrangements to open up and release its genome[5–7]. Because expulsion of the pocket factor is required for infection, a molecule that replaces this factor with higher affinity can serve as an antiviral agent that acts before the virus can replicate. Here, we present the crystal structure of CVA16 in complex with the capsid binder 3-( 4-pyridyl)-2-imidazolidinone( GPP3)( Fig 1b), and calculate the energy of the compound/protein interaction using an in silico docking method. The same in silico protocol is used to dock two recently designed capsid binders[8] into the CVA16 crystal structure to demonstrate that they have a similar binding mode. Furthermore, the structural and in silico results are analyzed in the context of the antiviral activity of these inhibitors against a wide range of enteroviruses, showing the potency and broad-spectrum antiviral activity of these molecules.
Discussion:
One of the most promising strategies to prevent infection with enteroviruses is to replace the hydrophobic-pocket-factors with more robust, high-affinity pocket binders[5, 8]. We investigated the interaction of GPP3 with CVA16 by determining the crystal structure of it in complex with the whole virus particle and identified the key residues involved in the interactions with the capsid binder including Phe135 and Tyr155 which make a hydrophobic sandwich with the phenoxy moiety as observed for EV71[8]. The QMPLD[12] method, with guidance from the observed crystal structures, provided reliable docking results and identified the residues in the CVA16 pocket interacting with NLD and ALD. We supported these structural results with virus-cell-based assays using the respective inhibitors. The EC50 measurements performed with these inhibitors against CVA16, showed for NLD an EC50 of 0. 12 nM. Additionally, we tested the activity of these inhibitors against a panel of enteroviruses( Table 2). Finally, structural comparisons( Fig 9) were used in a meta-analysis to correlate structural features with differences in antiviral activity. These results reinforce the potential of NLD as a candidate for a HFMD drug. We also rationalized the results for other viruses: low activity generally accompanies replacement of a Phe with Leu which fails to make the proper hydrophobic sandwich with the phenoxy moiety present in all inhibitors or the presence of side chains cluttering the entrance of the pocket interfering with the binding of the inhibitors. Good anti-poliovirus activity was observed for all the three capsid binders with highest EC50 for PV1 which has a Leu residue at the bottom of the pocket, that reduces the energy of binding, compared to PV2 and PV3, which have a Phe. In conclusion, the hydrophobic pocket below the canyon in VP1 still proves an interesting target for the development of novel inhibitors that target the early stage of enterovirus infection.
Hand , foot and mouth disease ( HFMD ) , a common infectious disease of children documented worldwide is caused by enterovirus infection . Coxsackievirus A16 ( CVA16 ) and enterovirus 71 ( EV71 ) are the major causative agents of HFMD . Although EV71 vaccines have completed phase III clinical trials , there remains no vaccine against CVA16 or licensed drug against either CVA16 or EV71 . In this study we show the crystal structure of CVA16 in complex with inhibitor GPP3 , shedding light on the residues involved in the interaction with the virus capsid . Taking advantage of the crystal structure we employed a quantum mechanics polarized ligand docking ( QMPLD ) protocol to dock two recently designed capsid binders . These molecules have been already proven to be very powerful inhibitors of EV71 and here we show that they exhibit strong antiviral activity against a wide range of enterovirus . Our research provides new insights into the design of inhibitors for the treatment of different pathogenic enterovirus infections .