Optimization of 1,3-disubstituted urea-based inhibitors of Zika virus infection |
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| Institution: | 1. Department of Pathology and Laboratory Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;2. Department of Radiation Oncology, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;3. David Geffen School of Medicine at UCLA, Volunteering Program, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;4. Jonsson Comprehensive Cancer Center, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;5. UCLA AIDS Institute, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA;6. Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, 760 Westwood Plaza, Los Angeles, CA 90024, USA;7. The Pasarow Mass Spectrometry Laboratory, The Jane and Terry Semel Institute for Neuroscience and Human Behavior, 760 Westwood Plaza, Los Angeles, CA 90024, USA;1. Discovery Sciences, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA;2. Cardiovascular & Metabolic Research, Janssen Research & Development, L.L.C., Welsh & McKean Roads, Spring House, PA 19477, USA;1. Centro de Investigación en Sanidad Animal – INIA, Valdeolmos 28130, Madrid, Spain;2. Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), Cantoblanco 28049, Madrid, Spain;1. Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow 117997, Russia;2. Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia;3. Department of Biology and Biotechnology, National Research University Higher School of Economics, Moscow 117312, Russia;4. FSBSI «Chumakov FSC R&D IBP RAS», Moscow 108819, Russia;5. Mendeleev University of Chemical Technology, Moscow 125047, Russia;6. Institute of Physico-Organic Chemistry, Minsk 220072, Belarus;7. Gause Institute of New Antibiotics, Moscow 119021, Russia;8. Institute of Translational Medicine and Biotechnology, Sechenov First Moscow State Medical University, Moscow 119991, Russia;1. Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China;2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China;3. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China;1. School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, ROC;2. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, ROC;3. Department of Biological Sciences, National University of Singapore, Singapore, Singapore;4. Institute of Infectious Diseases and Vaccinology, National Health Research Institute, Miaoli, Taiwan, ROC;5. Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC;6. Department of Pharmacy Practice, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC;7. Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan, ROC |
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| Abstract: | Zika virus (ZIKV) has become a public health concern worldwide due to its association with congenital abnormalities and neurological diseases. To date, no effective vaccines or antiviral drugs have been approved for the treatment of ZIKV infection, and new inexpensive therapeutic options are urgently needed. In this study, we have used an in vitro plaque assay to assess an antiviral activity of the second generation of anti-ZIKV compounds, based on 1,3-disubstituted (thio)urea scaffold. Several compounds in the library were found to possess excellent activity against Zika virus with IC50 values <200 pM. The most active analog, A5 exhibited an exceptional IC50 = 85.1 ± 1.7 pM. Further analysis delineated structural requirements necessary for potent antiviral effects of this class of compounds. Collectively, our findings suggest that 1,3-disubstituted (thio)urea derivatives are excellent preclinical candidates for the development of anti-ZIKV therapeutics. |
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| Keywords: | Antivirals Zika inhibitors Zika virus Plaque assay |
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