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      Research progress on repositioning drugs and specific therapeutic drugs for SARS-CoV-2

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          Abstract

          SARS-CoV-2 has been widely spread around the world and COVID-19 was declared a global pandemic by the World Health Organization. Limited clinically effective antiviral drugs are available now. The development of anti-SARS-CoV-2 drugs has become an urgent work worldwide. At present, potential therapeutic targets and drugs for SARS-CoV-2 are continuously reported, and many repositioning drugs are undergoing extensive clinical research, including remdesivir and chloroquine. On the other hand, structures of many important viral target proteins and host target proteins, including that of RdRp and Mpro were constantly reported, which greatly promoted structure-based drug design. This paper summarizes the current research progress and challenges in the development of anti-SARS-CoV-2 drugs, and proposes novel short-term and long-term drug research strategies.

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          Most cited references 10

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          Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease

          SARS-CoV-2 is the etiological agent responsible for the global COVID-19 outbreak. The main protease (Mpro) of SARS-CoV-2 is a key enzyme that plays a pivotal role in mediating viral replication and transcription. We designed and synthesized two lead compounds (11a and 11b) targeting Mpro. Both exhibited excellent inhibitory activity and potent anti-SARS-CoV-2 infection activity. The X-ray crystal structures of SARS-CoV-2 Mpro in complex with 11a or 11b, both determined at 1.5 Å resolution, showed that the aldehyde groups of 11a and 11b are covalently bound to Cys145 of Mpro. Both compounds showed good PK properties in vivo, and 11a also exhibited low toxicity, suggesting that these compounds are promising drug candidates.
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            Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.

            Outbreaks of Ebola hemorrhagic fever in sub-Saharan Africa are associated with case fatality rates of up to 90%. Currently, neither a vaccine nor an effective antiviral treatment is available for use in humans. Here, we evaluated the efficacy of the pyrazinecarboxamide derivative T-705 (favipiravir) against Zaire Ebola virus (EBOV) in vitro and in vivo. T-705 suppressed replication of Zaire EBOV in cell culture by 4log units with an IC90 of 110μM. Mice lacking the type I interferon receptor (IFNAR(-)(/)(-)) were used as in vivo model for Zaire EBOV-induced disease. Initiation of T-705 administration at day 6 post infection induced rapid virus clearance, reduced biochemical parameters of disease severity, and prevented a lethal outcome in 100% of the animals. The findings suggest that T-705 is a candidate for treatment of Ebola hemorrhagic fever. Copyright © 2014 The Authors. Published by Elsevier B.V. All rights reserved.
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              Drug repurposing strategies for COVID-19

              COVID-19 has now been declared a pandemic and new treatments are urgently needed as we enter a phase beyond containment. Developing new drugs from scratch is a lengthy process, thus impractical to face the immediate global challenge. Drug repurposing is an emerging strategy where existing medicines, having already been tested safe in humans, are redeployed to combat difficult-to-treat diseases. While using such repurposed drugs individually may ultimately not yield a significant clinical benefit, carefully combined cocktails could be very effective, as was for HIV in the 1990s; the urgent question now being which combination.
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                Author and article information

                Journal
                Future Med Chem
                Future Med Chem
                FMC
                Future Medicinal Chemistry
                Newlands Press Ltd (London, UK )
                1756-8919
                1756-8927
                08 July 2020
                June 2020
                08 July 2020
                Affiliations
                1National Engineering Research Center For The Emergency Drug, Beijing Institute of Pharmacology & Toxicology, Beijing, 100850, China
                Author notes
                [* ]Author for correspondence: zhouxinbo@ 123456bmi.ac.cn
                [** ]Author for correspondence: zhongwu@ 123456bmi.ac.cn
                [‡]

                Authors contributed equally

                Article
                10.4155/fmc-2020-0158
                7341957
                32638628
                © 2020 Newlands Press

                This work is licensed under the Creative Commons Attribution 4.0 License

                Page count
                Pages: 14
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