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      Teriflunomide: A possible effective drug for the comprehensive treatment of COVID-19

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          Abstract

          The coronavirus disease 2019 (COVID-19) pandemic has undoubtedly become a global crisis. Consequently, discovery and identification of new or known potential drug candidates to solve the health problems caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become an urgent necessity. This current research study sheds light on the possible direct repurposing of the antirheumatic drug teriflunomide to act as an effective and potent anti-SARS-CoV-2 agent. Herein, an interesting computational molecular docking study of teriflunomide, to investigate and evaluate its potential inhibitory activities on the novel coronaviral-2 RNA-dependent RNA polymerase (nCoV-RdRp) protein, was reported. The docking procedures were accurately carried out on nCoV-RdRp (with/without RNA) using the COVID-19 Docking Server, through adjusting it on the small molecule docking mode. Remdesivir and its active metabolite (GS-441524) were used as the active references for the comparison and evaluation purpose. Interestingly, the computational docking analysis of the best inhibitory binding mode of teriflunomide in the binding pocket of the active site of the SARS-CoV-2 RdRp revealed that teriflunomide may exhibit significantly stronger inhibitory binding interactions and better inhibitory binding affinities (teriflunomide has considerably lower binding energies of −9.70 and −7.80 kcal/mol with RdRp-RNA and RdRp alone, respectively) than both references. It was previously reported that teriflunomide strongly inhibits the viral replication and reproduction through two mechanisms of action, thus the results obtained in the present study surprisingly supports the double mode of antiviral action of this antirheumatic ligand. In conclusion, the current research paved the way to practically prove the hypothetical theory of the promising abilities of teriflunomide to successfully attack the SARS-CoV-2 particles and inhibit their replication in a triple mode of action through integrating the newly-discovered nCoV-RdRp-inhibiting properties with the previously-known two anticoronaviral mechanisms of action. Based on the previous interesting facts and results, the triple SARS-CoV-2/sextet COVID-19 attacker teriflunomide can further undergo in vitro/ in vivo anti-COVID-19 assays together with preclinical/clinical studies and trials in an attempt to evaluate and prove its comprehensive pharmacological activities against the different SARS-CoV-2 strains to be effectively used in COVID-19 therapy in the very near future.

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          The continuing 2019-nCoV epidemic threat of novel coronaviruses to global health — The latest 2019 novel coronavirus outbreak in Wuhan, China

          The city of Wuhan in China is the focus of global attention due to an outbreak of a febrile respiratory illness due to a coronavirus 2019-nCoV. In December 2019, there was an outbreak of pneumonia of unknown cause in Wuhan, Hubei province in China, with an epidemiological link to the Huanan Seafood Wholesale Market where there was also sale of live animals. Notification of the WHO on 31 Dec 2019 by the Chinese Health Authorities has prompted health authorities in Hong Kong, Macau, and Taiwan to step up border surveillance, and generated concern and fears that it could mark the emergence of a novel and serious threat to public health (WHO, 2020a, Parr, 2020). The Chinese health authorities have taken prompt public health measures including intensive surveillance, epidemiological investigations, and closure of the market on 1 Jan 2020. SARS-CoV, MERS-CoV, avian influenza, influenza and other common respiratory viruses were ruled out. The Chinese scientists were able to isolate a 2019-nCoV from a patient within a short time on 7 Jan 2020 and perform genome sequencing of the 2019-nCoV. The genetic sequence of the 2019-nCoV has become available to the WHO on 12 Jan 2020 and this has facilitated the laboratories in different countries to produce specific diagnostic PCR tests for detecting the novel infection (WHO, 2020b). The 2019-nCoV is a β CoV of group 2B with at least 70% similarity in genetic sequence to SARS-CoV and has been named 2019-nCoV by the WHO. SARS is a zoonosis caused by SARS-CoV, which first emerged in China in 2002 before spreading to 29 countries/regions in 2003 through a travel-related global outbreak with 8,098 cases with a case fatality rate of 9.6%. Nosocomial transmission of SARS-CoV was common while the primary reservoir was putatively bats, although unproven as the actual source and the intermediary source was civet cats in the wet markets in Guangdong (Hui and Zumla, 2019). MERS is a novel lethal zoonotic disease of humans endemic to the Middle East, caused by MERS-CoV. Humans are thought to acquire MERS-CoV infection though contact with camels or camel products with a case fatality rate close to 35% while nosocomial transmission is also a hallmark (Azhar et al., 2019). The recent outbreak of clusters of viral pneumonia due to a 2019-nCoV in the Wuhan market poses significant threats to international health and may be related to sale of bush meat derived from wild or captive sources at the seafood market. As of 10 Jan 2020, 41 patients have been diagnosed to have infection by the 2019-nCoV animals. The onset of illness of the 41 cases ranges from 8 December 2019 to 2 January 2020. Symptoms include fever (>90% cases), malaise, dry cough (80%), shortness of breath (20%) and respiratory distress (15%). The vital signs were stable in most of the cases while leucopenia and lymphopenia were common. Among the 41 cases, six patients have been discharged, seven patients are in critical care and one died, while the remaining patients are in stable condition. The fatal case involved a 61 year-old man with an abdominal tumour and cirrhosis who was admitted to a hospital due to respiratory failure and severe pneumonia. The diagnoses included severe pneumonia, acute respiratory distress syndrome, septic shock and multi-organ failure. The 2019-nCoV infection in Wuhan appears clinically milder than SARS or MERS overall in terms of severity, case fatality rate and transmissibility, which increases the risk of cases remaining undetected. There is currently no clear evidence of human to human transmission. At present, 739 close contacts including 419 healthcare workers are being quarantined and monitored for any development of symptoms (WHO, 2020b, Center for Health Protection and HKSAR, 2020). No new cases have been detected in Wuhan since 3 January 2020. However the first case outside China was reported on 13th January 2020 in a Chinese tourist in Thailand with no epidemiological linkage to the Huanan Seafood Wholesale Market. The Chinese Health Authorities have carried out very appropriate and prompt response measures including active case finding, and retrospective investigations of the current cluster of patients which have been completed; The Huanan Seafood Wholesale Market has been temporarily closed to carry out investigation, environmental sanitation and disinfection; Public risk communication activities have been carried out to improve public awareness and adoption of self-protection measures. Technical guidance on novel coronavirus has been developed and will continue to be updated as additional information becomes available. However, many questions about the new coronavirus remain. While it appears to be transmitted to humans via animals, the specific animals and other reservoirs need to be identified, the transmission route, the incubation period and characteristics of the susceptible population and survival rates. At present, there is however very limited clinical information of the 2019-nCoV infection and data are missing in regard to the age range, animal source of the virus, incubation period, epidemic curve, viral kinetics, transmission route, pathogenesis, autopsy findings and any treatment response to antivirals among the severe cases. Once there is any clue to the source of animals being responsible for this outbreak, global public health authorities should examine the trading route and source of movement of animals or products taken from the wild or captive conditions from other parts to Wuhan and consider appropriate trading restrictions or other control measures to limit. The rapid identification and containment of a novel coronavirus virus in a short period of time is a re-assuring and a commendable achievement by China’s public health authorities and reflects the increasing global capacity to detect, identify, define and contain new outbreaks. The latest analysis show that the Wuhan CoV cluster with the SARS CoV.10 (Novel coronavirus - China (01): (HU) WHO, phylogenetic tree Archive Number: 20200112.6885385). This outbreak brings back memories of the novel coronavirus outbreak in China, the severe acute respiratory syndrome (SARS) in China in 2003, caused by a novel SARS-CoV-coronavirus (World Health Organization, 2019a). SARS-CoV rapidly spread from southern China in 2003 and infected more than 3000 people, killing 774 by 2004, and then disappeared – never to be seen again. However, The Middle East Respiratory Syndrome (MERS) Coronavirus (MERS-CoV) (World Health Organization, 2019b), a lethal zoonotic pathogen that was first identified in humans in the Kingdom of Saudi Arabia (KSA) in 2012 continues to emerge and re-emerge through intermittent sporadic cases, community clusters and nosocomial outbreaks. Between 2012 and December 2019, a total of 2465 laboratory-confirmed cases of MERS-CoV infection, including 850 deaths (34.4% mortality) were reported from 27 countries to WHO, the majority of which were reported by KSA (2073 cases, 772 deaths. Whilst several important aspects of MERS-CoV epidemiology, virology, mode of transmission, pathogenesis, diagnosis, clinical features, have been defined, there remain many unanswered questions, including source, transmission and epidemic potential. The Wuhan outbreak is a stark reminder of the continuing threat of zoonotic diseases to global health security. More significant and better targeted investments are required for a more concerted and collaborative global effort, learning from experiences from all geographical regions, through a ‘ONE-HUMAN-ENIVRONMENTAL-ANIMAL-HEALTH’ global consortium to reduce the global threat of zoonotic diseases (Zumla et al., 2016). Sharing experience and learning from all geographical regions and across disciplines will be key to sustaining and further developing the progress being made. Author declarations All authors have a specialist interest in emerging and re-emerging pathogens. FN, RK, OD, GI, TDMc, CD and AZ are members of the Pan-African Network on Emerging and Re-emerging Infections (PANDORA-ID-NET) funded by the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Programme for Research and Innovation. AZ is a National Institutes of Health Research senior investigator. All authors declare no conflicts of interest.
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            Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

            SARS-CoV-2 has caused tens of thousands of infections and more than one thousand deaths. There are currently no registered therapies for treating coronavirus infections. Because of time consuming process of new drug development, drug repositioning may be the only solution to the epidemic of sudden infectious diseases. We systematically analyzed all the proteins encoded by SARS-CoV-2 genes, compared them with proteins from other coronaviruses, predicted their structures, and built 19 structures that could be done by homology modeling. By performing target-based virtual ligand screening, a total of 21 targets (including two human targets) were screened against compound libraries including ZINC drug database and our own database of natural products. Structure and screening results of important targets such as 3-chymotrypsin-like protease (3CLpro), Spike, RNA-dependent RNA polymerase (RdRp), and papain like protease (PLpro) were discussed in detail. In addition, a database of 78 commonly used anti-viral drugs including those currently on the market and undergoing clinical trials for SARS-CoV-2 was constructed. Possible targets of these compounds and potential drugs acting on a certain target were predicted. This study will provide new lead compounds and targets for further in vitro and in vivo studies of SARS-CoV-2, new insights for those drugs currently ongoing clinical studies, and also possible new strategies for drug repositioning to treat SARS-CoV-2 infections.
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              Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study

              An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and its caused coronavirus disease 2019 (COVID-19) has been reported in China since December 2019. More than 16% of patients developed acute respiratory distress syndrome, and the fatality ratio was about 1%–2%. No specific treatment has been reported. Herein, we examine the effects of Favipiravir (FPV) versus Lopinavir (LPV)/ritonavir (RTV) for the treatment of COVID-19. Patients with laboratory-confirmed COVID-19 who received oral FPV (Day 1: 1600 mg twice daily; Days 2–14: 600 mg twice daily) plus interferon (IFN)-α by aerosol inhalation (5 million U twice daily) were included in the FPV arm of this study, whereas patients who were treated with LPV/RTV (Days 1–14: 400 mg/100 mg twice daily) plus IFN-α by aerosol inhalation (5 million U twice daily) were included in the control arm. Changes in chest computed tomography (CT), viral clearance, and drug safety were compared between the two groups. For the 35 patients enrolled in the FPV arm and the 45 patients in the control arm, all baseline characteristics were comparable between the two arms. A shorter viral clearance time was found for the FPV arm versus the control arm (median (interquartile range, IQR), 4 (2.5–9) d versus 11 (8–13) d, P < 0.001). The FPV arm also showed significant improvement in chest imaging compared with the control arm, with an improvement rate of 91.43% versus 62.22% (P = 0.004). After adjustment for potential confounders, the FPV arm also showed a significantly higher improvement rate in chest imaging. Multivariable Cox regression showed that FPV was independently associated with faster viral clearance. In addition, fewer adverse reactions were found in the FPV arm than in the control arm. In this open-label nonrandomized control study, FPV showed significantly better treatment effects on COVID-19 in terms of disease progression and viral clearance; if causal, these results should be important information for establishing standard treatment guidelines to combat the SARS-CoV-2 infection.
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                Author and article information

                Journal
                Current Research in Pharmacology and Drug Discovery
                The Author. Published by Elsevier B.V.
                2590-2571
                2590-2571
                11 September 2021
                11 September 2021
                : 100055
                Affiliations
                [a ]Dr. Amgad Rabie's Research Lab. for Drug Discovery (DARLD), Mansoura, Egypt
                [b ]Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt
                Article
                S2590-2571(21)00042-0 100055
                10.1016/j.crphar.2021.100055
                8433057
                34870153
                d46b9819-aafe-4f77-87fc-29565c3d165c
                © 2021 The Author. Published by Elsevier B.V.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 26 July 2021
                : 30 August 2021
                : 8 September 2021
                Categories
                Article

                anti-covid-19/anti-sars-cov-2 drug,coronaviral-2 rna-dependent rna polymerase (rdrp),covid-19 cytokine storm,teriflunomide,leflunomide,remdesivir/gs-441524,computational molecular docking,drug discovery

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