The A-Z of Zika drug discovery

Abstract

Despite the recent outbreak of Zika virus (ZIKV), there are still no approved treatments, and early-stage compounds are probably many years away from approval. A comprehensive A-Z review of the recent advances in ZIKV drug discovery efforts is presented, highlighting drug repositioning and computationally guided compounds, including discovered viral and host cell inhibitors. Promising ZIKV molecular targets are also described and discussed, as well as targets belonging to the host cell, as new opportunities for ZIKV drug discovery. All this knowledge is not only crucial to advancing the fight against the Zika virus and other flaviviruses but also helps us prepare for the next emerging virus outbreak to which we will have to respond.

Figure 1

Scheme of Zika virus (ZIKV) surface, structural and nonstructural proteins. (a) Surface-shaded depth cued representation of mature ZIKV (built using UCSF Chimera package , http://www.rbvi.ucsf.edu/chimera, based on PDB ID 5IRE), showing the icosahedral-like symmetry arrangement of surface proteins. (b) Virion components, highlighting the E, M and C proteins, as well as genomic RNA. ZIKV encodes a large polyprotein, which after processing yields three structural proteins (C, M and E) and seven nonstructural proteins (NS1; NS2A; NS2B; NS3 protease and helicase domains; NS4A; NS4B; NS5 methyltransferase and RNA polymerase domains), built using the VMD program (http://www.ks.uiuc.edu/Research/vmd/). NS5 domains are represented separately, as two distinct targets, but NS5 methyltransferase is attached to the NS5 polymerase domain to form the full-length NS5. (c) ZIKV infectious life cycle: the virus is attached (1) and subsequently internalized (2) by receptor-mediated endocytosis. The virus is then trafficked to early endosomes, where the acidic environment induces fusion (3) between the virus and host membrane resulting in particle disassembly and genome release (4). RNA is replicated and translated into a single polyprotein, which is processed by host and virus-encoded proteins (5). Following translation, a replication complex is assembled and associated to virus-induced membranes where viral replication takes place (6). The progeny RNA (+) strands can either initiate a new translation cycle or be assembled into virions within the endoplasmic reticulum (ER) (7). The resultant immature virions are transported to the trans-Golgi where the immature virions are transformed into mature infectious particles (8) that are released by exocytosis (9). In the pink boxes are the names of the compounds that can inhibit the marked steps of the virus lifecycle.

Figure 2

Ribbon-representation of some of the ZIKV protein 3D structures. (a) NS2B–NS3 protease, highlighting the substrate/ligand-binding pocket occupied by a boronate inhibitor and the compound 1H-1,3-benzodiazol-1-ylmethanol . (b) NS3 helicase, highlighting the RNA and ATP binding sites . (c) NS5 methyltransferase domain, highlighting the active site, SAM/SAH- and GTP/cap-binding sites. (d) NS5 polymerase domain, emphasizing the active site, NTP and RNA binding sites. (e) Envelope protein and its β-barrel-shaped domain I (DI), finger-like domain II (DII), immunoglobulin-like domain III (DIII) and a ligand-binding pocket between DI and DIII . This predicted binding pocket encloses a hydrophobic cavity around the flexible linker joining DI and DIII. (f) Capsid protein , and the predicted ligand-binding pockets. All these 3D structures are available in PDB and the figures were built using the VMD program (http://www.ks.uiuc.edu/Research/vmd/).

Figure 3

Chemical structures of selected Zika virus (ZIKV) protein inhibitors. (a) Envelope glycoprotein inhibitor: nanchangmycin (IC₅₀ = 0.1 μM) . (b) NS2B–NS3 protease inhibitors: temoporfin (IC₅₀ = 1.1 μM) and NSC157058 (IC₅₀ = 0.82 μM) . (c) NS3 helicase inhibitor: suramin (EC₅₀ = 0.42 μM), which was tested only in a cell-based assay in ZIKV . (d) NS5 polymerase inhibitors: sofosbuvir (IC₅₀ = 7.3 μM) , 2-C-ethynyl-UTP (IC₅₀ = 0.46 μM) and DMB213 (IC₅₀ = 5.2 μM) . (e) NS5 methyltransferase inhibitor: sinefungin (IC₅₀ = 1.18 μM) , .