Drug Discovery Today Volume 00, Number 00 June 2018 REVIEWS Teaser Zika clinical outcomes might be nefarious impacting newborns for a lifetime. There is still no drug available to cure Zika. We provide guidance to help understand and advance the search for a cure. KEYNOTE REVIEW – The A Z of Zika drug discovery Reviews 1 1 1 Melina Mottin graduated Melina Mottin , Joyce V.V.B. Borba , Rodolpho C. Braga , in pharmacy and earned her 2,3 4 Master’s degree and PhD at Pedro H.M. Torres , Matheus C. Martini , University of Campinas 4 5 (UNICAMP), Brazil. The Jose Luiz Proenca-Modena , Carla C. Judice , main focus of her studies 5 6 7 was to apply molecular Fabio T.M. Costa , Sean Ekins , Alexander L. Perryman and dynamics simulations and 1,5 other computational Carolina Horta Andrade strategies for a nuclear receptor and its association with drugs and coregulatory proteins, implicated in diabetes. 1 LabMol – Laboratory for Molecular Modeling and Drug Design, Faculdade de Farmacia, Universidade Federal de Melina is currently Research Associate of the OpenZika project, at Federal University of Goias, mainly applying Goias – UFG, Goiânia, GO 74605-170, Brazil 2 virtual screening based on docking and QSAR models to Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ 21040-900, Brazil 3 select drug candidates against Zika virus. Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK 4 Alexander L. Perryman Laboratory of Emerging Viruses (LEVE), Department of Genetics, Evolution, Microbiology and Immunology, earned his PhD in Andy Institute of Biology, UNICAMP, Campinas, SP 13083-864, Brazil 5 McCammon’s lab at UCSD. Laboratory of Tropical Diseases – Prof. Dr. Luiz Jacintho da Silva, Department of Genetics, Evolution, Alex is now a senior Microbiology and Immunology, Institute of Biology, UNICAMP, Campinas, SP 13083-864, Brazil 6 researcher in the Collaborations Pharmaceuticals, Inc., 840 Main Campus Drive, Lab 3510, Raleigh, NC 27606, USA Freundlich lab, a Co- 7 Department of Pharmacology, Physiology and Neuroscience, Rutgers University–New Jersey Medical School, Principal Investigator of OpenZika and has Newark, NJ 07103, USA extensive training in developing and applying computational methods in drug discovery for infectious diseases. He is part of the Despite the recent outbreak of Zika virus (ZIKV), there are still no approved Center for Emerging & Re-emerging Pathogens at treatments, and early-stage compounds are probably many years away Rutgers-NJMS. He was a Research Associate in Art Olson’s lab at The Scripps Research Institute, where from approval. A comprehensive A–Z review of the recent advances in he ran the day-to-day operations of FightAIDS@Home, a project on IBM’s World ZIKV drug discovery efforts is presented, highlighting drug repositioning Community Grid. He also designed, led and ran the and computationally guided compounds, including discovered viral and largest computational drug discovery project on malaria: GO Fight Against Malaria. host cell inhibitors. Promising ZIKV molecular targets are also described Carolina Horta and discussed, as well as targets belonging to the host cell, as new Andrade is Associate Professor at Federal opportunities for ZIKV drug discovery. All this knowledge is not only University of Goias. She crucial to advancing the fight against the Zika virus and other flaviviruses graduated in pharmacy and earned her PhD in drugs but also helps us prepare for the next emerging virus outbreak to which we and medicines from will have to respond. University of Sao Paulo. Her research focuses on computer-aided drug design, aiming to discover new drug candidates for neglected tropical diseases and cancer. Moreover, cheminformatics tools and QSAR Introduction for the prediction of toxicity properties of chemical compounds are also her field of expertise. In 2014, she Zika virus (ZIKV) remains a global health concern. Originally discovered in Africa in 1947 [1], was awarded with the ‘For Women in Science’ award ZIKV became an epidemic 60 years later, reaching several tropical regions of the Americas, Africa from L’Ore´al-ABC-UNESCO and, in 2015, she and Asia. Despite causing mild symptoms such as fever, rashes and conjunctivitis, the major received the ‘International Rising Talents’ commendation from L’Ore´al–UNESCO. In 2016, she concern about ZIKV regards the severe neurological disorders, such as microcephaly, craniofacial was elected Affiliated Member of the Brazilian Academy of Sciences. She is the Principal Investigator of the OpenZika project, the largest computational drug discovery project on Zika virus. Corresponding author: Horta Andrade, C. ([email protected]), ([email protected]) 1359-6446/ã 2018 Elsevier Ltd. All rights reserved. https://doi.org/10.1016/j.drudis.2018.06.014 www.drugdiscoverytoday.com 1 Please cite this article in press as: Mottin, M. et al. The A–Z of Zika drug discovery, Drug Discov Today (2018), https://doi.org/10.1016/j.drudis.2018.06.014 DRUDIS-2277; No of Pages 15 REVIEWS Drug Discovery Today Volume 00, Number 00 June 2018 disproportion, spasticity, seizures, irritability and other brainstem Currently, neither a specific antiviral drug nor a vaccine is dysfunctions [2,3]. In 2016, infant head computed tomographic available for treating or preventing ZIKV infection. However, there findings, of subjects infected during pregnancy, confirmed the are several promising drug targets encoded by the virus or present causal relationship between microcephaly and Zika infection [3]. A in host cells. There have been several reports on compounds found recent study by Yuan and co-workers demonstrated that a single to have activity against ZIKV and its proteins. Here, we present a mutation (S139N) in the pre-membrane (prM) structural protein comprehensive A–Z review of the recent advances in ZIKV drug Reviews increased ZIKV infectivity in neural progenitor cells (NPCs), mak- design, including viral and host cell inhibitors and several experi- ing the virus more virulent [4]. This mutation arose in the French mental and computational techniques that have been applied in Polynesia strain, and it has contributed to the increased incidence these studies. This information will contribute to the design of KEYNOTE REVIEW of microcephaly and higher mortality in neonates, according to drugs against ZIKV and related viruses. experimental assays [4]. The disorders attributed to Zika infection mainly affect infants but can also impact adults. There have been Structural features of ZIKV proteins ZIKV-related cases of Guillain–Barre´ syndrome [5], myelitis [6], ZIKV is a spherical, enveloped virus, with an icosahedral-like uveitis [7] and meningoencephalitis [8] reported in adults. symmetry [9] (Fig. 1a). Belonging to the genus Flavivirus of the (a) (b) E dimer M protein 5ʹ 3ʹ C pr M E NS1 NS2 NS2B NS3pro NS3 hel NS4NS4B NS5 met NS5 pol C protein Genomic RNA (c) 1 2 Nanchangmycin 9 ST-148 Sofosbuvir MPA 2 C-ethynyl-UTP Endosome Brequinar ʹ DMB213 6-Azauridine 8 7DMA 25-Hydroxycholesterol Chloroquine 3 5 Golgi Obatoclax 6 Niclosamide 4 7 Bortezomib MG132 Cytoplasm NS5 pol NS3pro ER C pr M NS2 NS3 hel NS5 met NS4 NS2B NS4B E NS1 ER Nucleus Drug Discovery Today 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 [171], 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 [172] (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. 2 www.drugdiscoverytoday.com Please cite this article in press as: Mottin, M. et al. The A–Z of Zika drug discovery, Drug Discov Today (2018), https://doi.org/10.1016/j.drudis.2018.06.014 DRUDIS-2277; No of Pages 15 Drug Discovery Today Volume 00, Number 00 June 2018 REVIEWS Flaviviridae family [10], ZIKV carries a positive-sense single-strand- ZIKV protein 3D structures and their ligand and or substrate ed RNA genome, encoding a large polyprotein, which after proces- binding pockets. The substrate binding pocket of ZIKV sing by host and viral proteases yields three structural and seven NS2B/NS3 protease (NS2B residues: S81, D83, K54 and NS3pro nonstructural (NS) proteins (Fig. 1b). Envelope protein (E), mem- residues: D75, H51, S135, G133, G151, D129, Y161) (Fig. 2a) was brane protein (M), which is expressed as prM, the precursor to M, based on the co-crystallized compound 1H-1,3-benzodiazol-1- and capsid (C) are the structural proteins, which form the virion.