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      Drug Repositioning: New Approaches and Future Prospects for Life-Debilitating Diseases and the COVID-19 Pandemic Outbreak

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          Abstract

          Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing’s syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment.

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          Most cited references109

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          Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

          Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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            In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

            Abstract Background The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) first broke out in Wuhan (China) and subsequently spread worldwide. Chloroquine has been sporadically used in treating SARS-CoV-2 infection. Hydroxychloroquine shares the same mechanism of action as chloroquine, but its more tolerable safety profile makes it the preferred drug to treat malaria and autoimmune conditions. We propose that the immunomodulatory effect of hydroxychloroquine also may be useful in controlling the cytokine storm that occurs late-phase in critically ill SARS-CoV-2 infected patients. Currently, there is no evidence to support the use of hydroxychloroquine in SARS-CoV-2 infection. Methods The pharmacological activity of chloroquine and hydroxychloroquine was tested using SARS-CoV-2 infected Vero cells. Physiologically-based pharmacokinetic models (PBPK) were implemented for both drugs separately by integrating their in vitro data. Using the PBPK models, hydroxychloroquine concentrations in lung fluid were simulated under 5 different dosing regimens to explore the most effective regimen whilst considering the drug’s safety profile. Results Hydroxychloroquine (EC50=0.72 μM) was found to be more potent than chloroquine (EC50=5.47 μM) in vitro. Based on PBPK models results, a loading dose of 400 mg twice daily of hydroxychloroquine sulfate given orally, followed by a maintenance dose of 200 mg given twice daily for 4 days is recommended for SARS-CoV-2 infection, as it reached three times the potency of chloroquine phosphate when given 500 mg twice daily 5 days in advance. Conclusions Hydroxychloroquine was found to be more potent than chloroquine to inhibit SARS-CoV-2 in vitro.
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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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                Author and article information

                Journal
                Viruses
                Viruses
                viruses
                Viruses
                MDPI
                1999-4915
                22 September 2020
                September 2020
                : 12
                : 9
                : 1058
                Affiliations
                [1 ]School of Science, Monash University, Bandar Sunway, Subang Jaya 47500, Selangor Darul Ehsan, Malaysia; zylow1@ 123456student.monash.edu (Z.Y.L.); iaf1@ 123456student.monash.edu (I.A.F.)
                [2 ]Tropical Medicine & Biology Platform, Monash University, Subang Jaya 47500, Selangor Darul Ehsan, Malaysia
                Author notes
                [* ]Correspondence: sunil.lal@ 123456monash.edu
                Author information
                https://orcid.org/0000-0001-6213-6040
                https://orcid.org/0000-0003-3548-4853
                Article
                viruses-12-01058
                10.3390/v12091058
                7551028
                32972027
                bd723210-d7c7-4779-8f9a-a21f90546df9
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 July 2020
                : 21 August 2020
                Categories
                Review

                Microbiology & Virology
                drug repositioning,novel diseases,orphan diseases,drug personalisation,covid-19,hiv,cushing’s syndrome

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