Need for a Standardized Translational Drug Development Platform: Lessons Learned from the Repurposing of Drugs for COVID-19
Frauke AssmusJean‐Sélim DriouichRana AbdelnabiLaura VangeelFranck TouretAyorinde AdehinPalang ChotsiriMaxime CochinCaroline S. FooDirk JochmansSeungtaek KimLéa LucianiGrégory MoureauSoonju ParkPaul-Rémi PetitDavid ShumThanaporn WattanakulBirgit WeynandLaurent FraisseJean‐Robert IosetCharles E. MowbrayAndrew OwenRichard M. HoglundJoel TärningXavier de LamballerieAntoine NougairèdeJohan NeytsPeter SjöFanny EscudiéIvan ScandaleEric Chatelain
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Abstract:
In the absence of drugs to treat or prevent COVID-19, drug repurposing can be a valuable strategy. Despite a substantial number of clinical trials, drug repurposing did not deliver on its promise. While success was observed with some repurposed drugs (e.g., remdesivir, dexamethasone, tocilizumab, baricitinib), others failed to show clinical efficacy. One reason is the lack of clear translational processes based on adequate preclinical profiling before clinical evaluation. Combined with limitations of existing in vitro and in vivo models, there is a need for a systematic approach to urgent antiviral drug development in the context of a global pandemic. We implemented a methodology to test repurposed and experimental drugs to generate robust preclinical evidence for further clinical development. This translational drug development platform comprises in vitro, ex vivo, and in vivo models of SARS-CoV-2, along with pharmacokinetic modeling and simulation approaches to evaluate exposure levels in plasma and target organs. Here, we provide examples of identified repurposed antiviral drugs tested within our multidisciplinary collaboration to highlight lessons learned in urgent antiviral drug development during the COVID-19 pandemic. Our data confirm the importance of assessing in vitro and in vivo potency in multiple assays to boost the translatability of pre-clinical data. The value of pharmacokinetic modeling and simulations for compound prioritization is also discussed. We advocate the need for a standardized translational drug development platform for mild-to-moderate COVID-19 to generate preclinical evidence in support of clinical trials. We propose clear prerequisites for progression of drug candidates for repurposing into clinical trials. Further research is needed to gain a deeper understanding of the scope and limitations of the presented translational drug development platform.Keywords:
Drug repositioning
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Tocilizumab
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Background: Science of medicine in the post-genomic era has significantly enhanced the knowledge of human diseases. These advancements could shed light to the translation of these benefits into drug therapeutics. Drug repurposing is a strategy that plays a pivotal role to provide novel insights into disease biology and further drive drug discovery as the ultimate goal. Herein, the current study aimed to analyse the global trends of drug repurposing peer-review publications from 2003 until 2022. Methods: We retrieved 1.371 articles related to drug repurposing studies and used similar terms and keywords, including “drug repositioning”, “drug repurposing”, “drug reprofiling”, “drug reusing”, and “drug recycling”. Results: The number of drug repurposing publications has increased dramatically from 2003 through 2022. Besides, the most active country in publishing drug repurposing research is the United States, followed by China, India, the United Kingdom, and Italy, respectively. Meanwhile, the top five frequently used keywords are drug repurposing (n = 336), drug repositioning (n = 335), COVID-19 (n = 134), SARS-CoV-2 (n = 135), and molecular docking (n = 67). Conclusions: This study emphasizes the importance of conducting active research collaboration in drug repurposing and drug repositioning especially pertaining to the COVID-19 pandemic.
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Abstract Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.
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Abstract PURPOSE Systematic repurposing of approved medicine for another indication represents an attractive strategy to accelerating drug development in oncology. Herein we present a strategy of combining biomarker testing with drug repurposing to identify new treatments for patients with advanced cancer. METHODS Tumours were sequenced with Illumina TruSight Oncology 500 (TSO-500) platform or the FoundationOne® CDx panel. Mutations were manually screened by two medical oncology clinicians and pathogenic mutations were categorised with reference to the literature. Variants of unknown significance were classified as potentially pathogenic if a plausible mechanism and computational prediction of pathogenicity existed. Gain of function mutations were evaluated through the repurposing databases Probe Miner, the Broad Institute Drug Repurposing Hub (Broad Institute DRH) and TOPOGRAPH. Gain of function mutations were classified as repurposing events if they were identified in Probe Miner, were not indexed in TOPOGRAPH which captures active clinical trial biomarkers and excluding mutations for which a known FDA-approved biomarker label exists. The performance of the computational repurposing approach was validated by evaluating its ability to identify known FDA-approved biomarkers. Exploratory functional analyses were performed with gene expression data and CRISPR-dependency data sourced from the DepMap portal. The total repurposable genome was identified by evaluating all possible gene-FDA drug approved combinations in the Probe Miner dataset. RESULTS The computational repurposing approach was highly accurate at identifying FDA therapies with known biomarkers (94%). Using a real-world dataset of next-generation sequencing molecular reports (n = 94) and excluding the identification of mutations that would render patients eligible for FDA-licensed therapies or local clinical trials, it was found that a meaningful percentage of patients (14%) would have an off-label therapeutic identified through this approach. Exploratory analyses were performed, including the identification of drug-target interactions that have been previously described in the medicinal chemistry literature but are not well known, and the evaluation of the frequency of theoretical drug repurposing events in the TCGA pan-cancer dataset (73% of samples in the cohort). CONCLUSION Overall, a computational drug repurposing approach may assist in identifying novel repurposing events in cancer patients with advanced tumours and no access to standard therapies. Further validation is needed to confirm the utility of a precision oncology approach using drug repurposing.
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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines.
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Drug repurposing is an unconventional approach that is used to investigate new therapeutic aids of existing and shelved drugs. Recent advancement in technologies and the availability of the data of genomics, proteomics, transcriptomics, etc., and with the accessibility of large and reliable database resources, there are abundantly of opportunities to discover drugs by drug repurposing in an efficient manner. The recent pandemic of SARS-COV-2, that caused the death of 6,245,750 human beings to date, has tremendously increase the exceptional usage of bioinformatics tools in interpreting the molecular characterizations of viral infections. In this paper, we have employed various bioinformatics tools such as AutoDock-Vina, PyMol etc. We have found a leading drug candidate Cepharanthine that has shown better results and effectiveness than recently used antiviral drug candidates such as Favipiravir, IDX184, Remedesivir, Ribavirin and etc. This paper has analyzed Cepharanthine potential therapeutic importance as a drug of choice in managing COVID-19 cases. It is anticipated that proposed study would be beneficial for researchers and medical practitioners in handling SARS-CoV-2 and its variant related diseases.
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Repurposing drugs (DR) has become a viable approach to hasten the search for cures for neurodegenerative diseases (NDs). This review examines different off-target and on-target drug discovery techniques and how they might be used to find possible treatments for non-diagnostic depressions. Off-target strategies look at the known or unknown side effects of currently approved drugs for repositioning, whereas on-target strategies connect disease pathways to targets that can be treated with drugs. The review highlights the potential of experimental and computational methodologies, such as machine learning, proteomic techniques, network and genomics-based approaches, and in silico screening, in uncovering new drug-disease correlations. It also looks at difficulties and failed attempts at drug repurposing for NDs, highlighting the necessity of exact and standardised procedures to increase success rates. This review's objectives are to address the purpose of drug repurposing in human disorders, particularly neurological diseases, and to provide an overview of repurposing candidates that are presently undergoing clinical trials for neurological conditions, along with any possible causes and early findings. We then include a list of drug repurposing strategies, restrictions, and difficulties for upcoming research.
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Drug repurposing is a strategy to study drugs that are approved to treat one condition or disease to check if they are effective as well as safe for treating other diseases. For a given indication, this strategy offers wide range of benefits over developing an entirely new drug. Repurposing of drugs is effective enough to minimize the time and costs in drug development since data is already available on their potential toxicity, formulation and pharmacology. Computational research in drug based industries is thought to have an effective approach for Research and Development process to accelerate the rate of drug designing at molecular level. Such an approach has already led to the identification and experimental validation of novel therapeutic indications. Drug repurposing can be forecasted using various machine learning models based on different entities. In this study, we present a strategy to drug repurposing by predicting indication for a specific disease based on expression profiles of drugs, with a focus on oncogenes. The availability of high-performance computing, and databases of various forms have also enhanced the ability to pose reasonable and testable hypotheses for drug repurposing, rescue, and repositioning. Drug repurposing is being considered as a supervised learning problem and applying distinct state-of-the-art machine learning methods for prediction. Drugs that are not initially indicated for a specific disease but have high predicted probabilities serve as superior candidates for repurposing.
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Viral diseases are responsible for several deaths around the world. Over the past few years, the world has seen several outbreaks caused by viral diseases that, for a long time, seemed to possess no risk. These are diseases that have been forgotten for a long time and, until nowadays, there are no approved drugs or vaccines, leading the pharmaceutical industry and several research groups to run out of time in the search for new pharmacological treatments or prevention methods. In this context, drug repurposing proves to be a fast and economically viable technique, considering the fact that it uses drugs that have a well-established safety profile. Thus, in this review, we present the main advances in drug repurposing and their benefit for searching new treatments against emerging viral diseases.We conducted a search in the bibliographic databases (Science Direct, Bentham Science, PubMed, Springer, ACS Publisher, Wiley, and NIH's COVID-19 Portfolio) using the keywords "drug repurposing", "emerging viral infections" and each of the diseases reported here (CoV; ZIKV; DENV; CHIKV; EBOV and MARV) as an inclusion/exclusion criterion. A subjective analysis was performed regarding the quality of the works for inclusion in this manuscript. Thus, the selected works were those that presented drugs repositioned against the emerging viral diseases presented here by means of computational, high-throughput screening or phenotype-based strategies, with no time limit and of relevant scientific value.291 papers were selected, 24 of which were CHIKV; 52 for ZIKV; 43 for DENV; 35 for EBOV; 10 for MARV; and 56 for CoV and the rest (72 papers) related to the drugs repurposing and emerging viral diseases. Among CoV-related articles, most were published in 2020 (31 papers), updating the current topic. Besides, between the years 2003 - 2005, 10 articles were created, and from 2011 - 2015, there were 7 articles, portraying the outbreaks that occurred at that time. For ZIKV, similar to CoV, most publications were during the period of outbreaks between the years 2016 - 2017 (23 articles). Similarly, most CHIKV (13 papers) and DENV (14 papers) publications occur at the same time interval. For EBOV (13 papers) and MARV (4 papers), they were between the years 2015 - 2016. Through this review, several drugs were highlighted that can be evolved in vivo and clinical trials as possible used against these pathogens showed that remdesivir represent potential treatments against CoV. Furthermore, ribavirin may also be a potential treatment against CHIKV; sofosbuvir against ZIKV; celgosivir against DENV, and favipiravir against EBOV and MARV, representing new hopes against these pathogens.The conclusions of this review manuscript show the potential of the drug repurposing strategy in the discovery of new pharmaceutical products, as from this approach, drugs could be used against emerging viral diseases. Thus, this strategy deserves more attention among research groups and is a promising approach to the discovery of new drugs against emerging viral diseases and also other diseases.
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