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Advances in Developing Therapies to Combat Zika Virus: Current Knowledge and Future Perspectives Ashok Munjal Old Dominion University ODU Digital Commons Bioelectrics Publications Frank Reidy Research Center for Bioelectrics 8-2017 Advances in Developing Therapies to Combat Zika Virus: Current Knowledge and Future Perspectives Ashok Munjal Rekha Khandia Kuldeep Dharma Swati Sachan Kumaragurubaran Karthik See next page for additional authors Follow this and additional works at: https://digitalcommons.odu.edu/bioelectrics_pubs Part of the Public Health Commons, Virology Commons, and the Virus Diseases Commons Repository Citation Munjal, Ashok; Khandia, Rekha; Dharma, Kuldeep; Sachan, Swati; Karthik, Kumaragurubaran; Tiwari, Ruchi; Malik, Yashpal S.; Kumar, Deepak; Singh, Raj K.; Iqbal, Hafiz M. N.; and Joshi, Sunil K., "Advances in Developing Therapies to Combat Zika Virus: Current Knowledge and Future Perspectives" (2017). Bioelectrics Publications. 132. https://digitalcommons.odu.edu/bioelectrics_pubs/132 Original Publication Citation Munjal, A., Khandia, R., Dhama, K., Sachan, S., Karthik, K., Tiwari, R., . Joshi, S. K. (2017). Advances in developing therapies to combat zika virus: Current knowledge and future perspectives. Frontiers in Microbiology, 8, 1469. doi:10.3389/fmicb.2017.01469 This Article is brought to you for free and open access by the Frank Reidy Research Center for Bioelectrics at ODU Digital Commons. It has been accepted for inclusion in Bioelectrics Publications by an authorized administrator of ODU Digital Commons. For more information, please contact [email protected]. Authors Ashok Munjal, Rekha Khandia, Kuldeep Dharma, Swati Sachan, Kumaragurubaran Karthik, Ruchi Tiwari, Yashpal S. Malik, Deepak Kumar, Raj K. Singh, Hafiz M. N. Iqbal, and Sunil K. Joshi This article is available at ODU Digital Commons: https://digitalcommons.odu.edu/bioelectrics_pubs/132 fmicb-08-01469 August 2, 2017 Time: 17:39 # 1 REVIEW published: 03 August 2017 doi: 10.3389/fmicb.2017.01469 Advances in Developing Therapies to Combat Zika Virus: Current Knowledge and Future Perspectives Ashok Munjal1, Rekha Khandia1, Kuldeep Dhama2*, Swati Sachan3, Kumaragurubaran Karthik4, Ruchi Tiwari5, Yashpal S. Malik6, Deepak Kumar7, Raj K. Singh8, Hafiz M. N. Iqbal9 and Sunil K. Joshi10 1 Department of Biochemistry and Genetics, Barkatullah University, Bhopal, India, 2 Division of Pathology, ICAR-Indian Veterinary Research Institute, Bareilly, India, 3 Immunology Section, ICAR-Indian Veterinary Research Institute, Bareilly, India, 4 Central University Laboratory, Tamil Nadu Veterinary and Animal Sciences University, Chennai, India, 5 Department of Veterinary Microbiology and Immunology, College of Veterinary Sciences, UP Pandit Deen Dayal Upadhayay Pashu Chikitsa Vigyan Vishwavidyalay Evum Go-Anusandhan Sansthan, Mathura, India, 6 Division of Biological Standardization, ICAR-Indian Veterinary Research Institute, Bareilly, India, 7 Division of Veterinary Biotechnology, ICAR-Indian Veterinary Research Institute, Bareilly, India, 8 ICAR-Indian Veterinary Research Institute, Bareilly, India, 9 School of Engineering and Science, Tecnologico de Monterrey, Campus Monterrey, Monterrey, Mexico, 10 Cellular Immunology Lab, Frank Reidy Research Center of Bioelectrics, Old Dominion University, Norfolk, VA, United States Zika virus (ZIKV) remained largely quiescent for nearly six decades after its first appearance in 1947. ZIKV reappeared after 2007, resulting in a declaration of an international “public health emergency” in 2016 by the World Health Organization Edited by: (WHO). Until this time, ZIKV was considered to induce only mild illness, but it Rubén Bueno-Marí, Universitat de València, Spain has now been established as the cause of severe clinical manifestations, including Reviewed by: fetal anomalies, neurological problems, and autoimmune disorders. Infection during A. Arturo Leis, pregnancy can cause congenital brain abnormalities, including microcephaly and Methodist Rehabilitation Center, United States neurological degeneration, and in other cases, Guillain-Barré syndrome, making Juan-Carlos Saiz, infections with ZIKV a substantial public health concern. Genomic and molecular Instituto Nacional de Investigación y investigations are underway to investigate ZIKV pathology and its recent enhanced Tecnología Agraria y Alimentaria, Spain pathogenicity, as well as to design safe and potent vaccines, drugs, and therapeutics. *Correspondence: This review describes progress in the design and development of various anti- Kuldeep Dhama ZIKV therapeutics, including drugs targeting virus entry into cells and the helicase [email protected] protein, nucleosides, inhibitors of NS3 protein, small molecules, methyltransferase Specialty section: inhibitors, interferons, repurposed drugs, drugs designed with the aid of computers, This article was submitted to neutralizing antibodies, convalescent serum, antibodies that limit antibody-dependent Virology, a section of the journal enhancement, and herbal medicines. Additionally, covalent inhibitors of viral protein Frontiers in Microbiology expression and anti-Toll-like receptor molecules are discussed. To counter ZIKV- Received: 13 June 2017 associated disease, we need to make rapid progress in developing novel therapies that Accepted: 20 July 2017 Published: 03 August 2017 work effectually to inhibit ZIKV. Citation: Keywords: Zika virus, drugs, therapies, microcephaly, Guillain-Barré Syndrome Munjal A, Khandia R, Dhama K, Sachan S, Karthik K, Tiwari R, Malik YS, Kumar D, Singh RK, INTRODUCTION Iqbal HMN and Joshi SK (2017) Advances in Developing Therapies Zika virus (ZIKV) is a mosquito-borne virus belonging to the Spondweni serocomplex in the to Combat Zika Virus: Current Knowledge and Future Perspectives. genus Flavivirus of the family Flaviviridae that has become a new threat following the Ebola Front. Microbiol. 8:1469. virus epidemic (Singh et al., 2016). The expanding ZIKV epidemic was declared an emergency doi: 10.3389/fmicb.2017.01469 by the World Health Organization on February 1, 2016 (Fajardo et al., 2016; WHO, 2016). Frontiers in Microbiology| www.frontiersin.org 1 August 2017| Volume 8| Article 1469 fmicb-08-01469 August 2, 2017 Time: 17:39 # 2 Munjal et al. Drugs and Therapies Countering Zika Virus ZIKV is a single-stranded RNA virus that encodes a single The convalescent stage ends with establishment of long lasting polyprotein that is cleaved to form mature proteins, i.e., the immunity (Gao et al., 2016). capsid, envelope (E), and precursor of membrane and non- Zika virus vaccines in development include inactivated structural proteins. Other flaviviruses such as dengue virus virus, nucleic acid-based vaccines (DNA or RNA), live vector (DENV), yellow fever virus (YFV), and West Nile virus (WNV) vaccines, subunit vaccines, virus-like particles, and recombinant are closely related to ZIKV. In the last six decades since its ZIKV. Because of its devastating effects, effective therapeutic discovery, ZIKV has been considered a mild human pathogen, agents and a vaccine are urgently needed. Presently, there are but recently it has emerged as threat to global health, showing several drugs reported to be useful in treating ZIKV, a few increased virulence, rapid spread, and an association with of which are repurposed drugs. Efforts to develop effective microcephaly and grave neurological complications like Guillain- drugs have increased worldwide, and a few compounds are Barré syndrome (GBS) (Cao-Lormeau et al., 2016; Carteaux et al., in phase I trials (Alam et al., 2017; Ali et al., 2017). The 2016; Mlakar et al., 2016; Sarno et al., 2016). present review discusses recent advances in and prospects for Zika virus has a wide tissue tropism in an experimental rhesus the design and development of various anti-viral drugs and macaque model, infecting the hemolymphatic system, lymph therapeutics for ZIKV infection, including the identification of nodes, spleen, cardiopulmonary, gastrointestinal, integument, novel drug targets. The updated information compiled here and genitourinary tissues, along with the adrenal gland, spinal will contribute to the design and development of additional cord, and cerebrospinal fluid (Coffey et al., 2017). Additionally, it effective drugs and pharmaceuticals to curtain the ill effects of has been reported in muscles, kidneys, bladders, and in excreted ZIKV. urine (Gourinat et al., 2015). In males, ZIKV can infect testes (Govero et al., 2016), prostate and seminal vesicles, explaining the long-term persistence of viremia in semen, even after virus is ADVANCES IN THE DESIGN AND no longer detectable in blood. In the female reproductive system, DEVELOPMENT OF ANTI-ZIKV DRUGS virus can be maintained in the vagina, uterus (Hirsch et al., 2017), AND THERAPIES vaginal epithelium (mice), and in uterine fibroblasts (Miner and Diamond, 2017). Miner and Diamond(2017) demonstrated the Specific anti-viral drugs are not yet available to combat ZIKV. wide tissue tropism of the virus in Hofbauer cells, trophoblasts, Acetaminophen is used to control fever and pain, anti-histamines and endothelial cells from the placenta. In addition, ZIKV was are used for pruritic rashes, and fluids are administered to found to infect the cornea, neurosensory retina, optic nerve, prevent dehydration in ZIKV-infected patients. However, certain aqueous humor, and tears. ZIKV infection in eyes results in drugs such as acetylsalicylic acid (aspirin) and non-steroidal uveitis (Furtado et al., 2016), and the persistence of the virus in anti-inflammatory drugs (NSAIDs) are contraindicated because cerebrospinal fluid and lymph nodes appears
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