Repurposing Drugs for Viruses and Cancer: A Novel Drug Repositioning Strategy for COVID-19

The high infection capacity and rapid mutations in coronavirus disease 2019 (COVID-19) has been no stranger to many. The etiological agent that contributed to this global health crisis is by no means the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 is characterized by an episode of immune fluctuations, followed by hyperactivation of inflammatory responses, known as the cytokine storm. The rapid progression of the COVID-19 pandemic calls for new and promising antiviral therapeutics. Repositioning anticancer drugs against the virus is very much explored due to the common similar pathways or targeting structures, opening new windows for many possibilities. As such, the repurposing of zidovudine for Friend leukemia virus and ouabain for Ebola virus are among the successful examples. Other potential FDA-approved anticancer drugs to be repositioned for COVID-19 include imatinib, saracatinib, and homoharringtonine, which have been studied for other coronaviruses in the past. Furthermore, current anticancer drugs like carmofur, carfilzomib, zotatifin, plitidepsin, and toremifene have gained interesting outcomes with respect to SARS-CoV-2. It is well recognized that to achieve viral replication, viruses antagonise or hijack host proteins and signaling pathways to gain productive infection, with SARS-CoV-2 indeed being no exception. This review aims to discuss the drug repositioning approaches concerning previously established anticancer drugs on viruses, especially on SARS-CoV-2. We accentuate this idea with specific examples of how potential anticancer inhibitors can effectively be used against SARS-CoV-2 as well as the limitations and future perspectives of drug repositioning. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023.

A comprehensive review on technological advances in alternate drug discovery process:Drug repurposing

The traditional de novo drug discovery is time consuming, costly and in some instances the drugs will fail to treat the disease which result in a huge loss to the organization. Drug repurposing is an alternative drug discovery process to overcome the limitations of the De novo drug discovery process. Ithelps for the identification of drugs to the rare diseases as well as in the pandemic situationwithin short span of time in a cost-effective way. The underlying principle of drug repurposing is that most of the drugs identified on a primary purpose have shown to treat other diseases also. One such example is Tocilizumab is primarily used for rheumatoid arthritis and it is repurposed to treat cancer and COVID-19. At present, nearly30% of the FDA approved drugs to treat various diseases are repurposed drugs. The drug repurposing is either drug-centric or disease centric and can be studied by using both experimental and in silico studies. The in silico repurpose drug discovery process is more efficient as it screens thousands of compounds from the diverse libraries within few days by various computational methods like Virtual screening, Docking, MD simulations,Machine Learning, Artificial Intelligence, Genome Wide Association Studies (GWAS), etc. with certain limitations.These limitationscan be addressed by effective integration of advanced technologies to identify a novel multi-purpose drug.Copyright © 2023, Association of Biotechnology and Pharmacy. All rights reserved.

In Silico Drug Repositioning for COVID-19: Progress and Challenges

he COVID-19 pandemic caused by SARS-CoV-2 has shown a rapid increase in the number of infected patients with a remarkable mortality rate, making it a global public health concern. Because there is currently no specific anti-viral drug for the treatment of COVID-19, repurposing of already approved drugs for other diseases may be explored. Drug repurposing has become a promising approach due to the opportunity to reduce development timelines and overall costs. In this chapter, we will discuss various computational drug repositioning strategies, the current COVID-19 treatment scenario, and challenges to the correct interpretation of existing preclinical/clinical evidence, as well as the generation of new evidence related to drug repurposing. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

Drug Repurposing in Oncology: A Systematic Review of Randomized Controlled Clinical Trials.

Quality pharmacological treatment can improve survival in many types of cancer. Drug repurposing offers advantages in comparison with traditional drug development procedures, reducing time and risk. This systematic review identified the most recent randomized controlled clinical trials that focus on drug repurposing in oncology. We found that only a few clinical trials were placebo-controlled or standard-of-care-alone-controlled. Metformin has been studied for potential use in various types of cancer, including prostate, lung, and pancreatic cancer. Other studies assessed the possible use of the antiparasitic agent mebendazole in colorectal cancer and of propranolol in multiple myeloma or, when combined with etodolac, in breast cancer. We were able to identify trials that study the potential use of known antineoplastics in other non-oncological conditions, such as imatinib for severe coronavirus disease in 2019 or a study protocol aiming to assess the possible repurposing of leuprolide for Alzheimer's disease. Major limitations of these clinical trials were the small sample size, the high clinical heterogeneity of the participants regarding the stage of the neoplastic disease, and the lack of accounting for multimorbidity and other baseline clinical characteristics. Drug repurposing possibilities in oncology must be carefully examined with well-designed trials, considering factors that could influence prognosis.

Drug Discovery and Big Data: From Research to the Community

Technology and artificial intelligence, alongside the COVID-19 pandemic vastly increasing technology use in health care, have precipitated an escalation of big data. Although real-world data (RWD) and real-world evidence (RWE) have contributed to determining outcomes outside the scope of randomized clinical trials (RCTs), RWD and RWE are underutilized in demonstrating drug effectiveness. Utilizing RWD may enhance the ability of regulatory agencies to approve drugs, provide drug effectiveness insight to payers, and improve personalized medicine. Additionally, RWD and RWE may assist in overcoming the limitations of RCT data such as treatment adherence and underrepresented patient subgroups and may support and expedite drug repositioning. Even though the limitations of using RWE and RWD include fragmented data context, poor data quality, and information governance, healthcare analytics hubs such as the European Health Data Space are designed to foster synergy among private and public healthcare players and may assist in overcoming these potential limitations. Such healthcare analytics hubs may enhance the utilization of RWE and/or RWD, which could ultimately result in better patient outcomes. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

Scientific debrief: cirrhosis

Globally, hepatitis C (26%), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from nonalcoholic fatty liver disease (8%) is small but increasing. Patients with acutely decompensated cirrhosis have a dismal prognosis and frequently progress to acuteon-chronic liver failure, which is characterised by hepatic and extrahepatic organ failure, Cardiovascular alterations including portal hypertension trigger the formation of portocaval shunts and varices. Systemic under filling and arterial hypotension is compensated by vasoconstriction but might decline into a state of aggravated portal hypertension and cirrhotic cardiomyopathy, leading to a hyperdynamic state, microvascular dysfunction and reduced organ perfusion culminating in decompensation. The immune system is dysfunctional showing a contrary co-existence of immune paralysis and immune overstimulation leading to secondary infections and inflammatory response syndrome aggravating cardiovascular alterations but also initiating tissue injury and metabolic alteration. This transition from compensated to decompensated cirrhosis is characterised by the occurrence of ascites, variceal bleeding and/or hepatic encephalopathy or organ failures (in the case of ACLF. Precipitating events for ACLF vary between Western countries (bacterial infection, alcohol intake) and Eastern countries (flare of HBV, superimposed HAV or HEV). In the majority of patients, systemic inflammation is a major driver of progression from compensated to decompensated cirrhosis. Once the first episode of AD develops, systemic inflammation follows a chronic course, with transient periods of aggravation due to proinflammatory precipitants or bursts of bacterial translocation resulting in repeated episodes of AD. The multistate model describing the clinical outcomes of decompensated cirrhosis has been well validated. State 3 is defined by the occurrence of variceal bleeding alone, state 4 by any single non-bleeding event, state 5 by any 2 or more events and the late decompensate state by any event with organ failures either with or without ACLF. 5-year mortality across states from 3 to 5 is in the order of, respectively: 20%, 30%, 88%. With late decompensation mortality ranges between 60 and 80% at 1 year. Cirrhosis is increasingly common and morbid. Optimal utilisation of therapeutic strategies to prevent and control the complications of cirrhosis are central to improving clinical and patient-reported outcomes. Aetiology-focused therapies that can prevent cirrhosis and its complications. These include anti-viral therapies, psychopharmacological therapy for alcohol-use disorder, management of hepatic encephalopathy (HE), ascites, hepatorenal syndrome, non-pain symptoms of cirrhosis including pruritis, muscle cramps, sexual dysfunction and fatigue, and reduce the risk of hepatocellular carcinoma. New disease-modifying agents are expected to be identified in the next few years by systematic drug repurposing and the development of novel molecules currently undergoing pre-clinical or early clinical testing. COVID-19 continues to pose a significant healthcare challenge throughout the world. Comorbidities including diabetes and hypertension are associated with a significantly higher mortality risk. Cirrhosis is associated with an increased risk of all-cause mortality in COVID-19 infection compared to non-cirrhotic patients. Patients with cirrhosis should be considered for targeted public health interventions to prevent COVID-19 infection, such as shielding and prioritisation of vaccination.

Drug repurposing and other strategies for rapid antiviral development: lessons from the early stage of the pandemic

The recent and recurrent spillover of three highly pathogenic coronaviruses, SARS-CoV-1, MERS-CoV and SARS-CoV-2, into human populations has stressed the importance of pandemic preparedness. Here, we describe how, in the absence of antiviral therapeutic options against coronaviruses, early clinical investigations have focused on the prompt repurposing of approved antiviral therapies. We discuss how, despite international collaborative efforts, their outcomes so far have been disappointing as none of the early drugs tested demonstrated effective clinical efficacy. We also outline innovative strategies and tools developed to fast-track development of novel classes of antivirals. These capitalise on a deeper understanding of viral molecular pathogenesis and how coronaviruses hijack the host cellular machinery to maximise their replication and counteract host defences. Collectively, these approaches are crucial to identify and validate novel targets for therapeutic interventions and expand the repertoire of broad-spectrum antiviral agents, so that these can be promptly deployed for current and future pandemics.Copyright © ERS 2021.

Application and mechanism of histamine receptor antagonists in treatment of Coronavirus disease 2019: research progress

The coronavirus disease 2019 (COVID-19) has become a global pandemic. It is urgent to find treatments to control the infection and improve symptoms. Homologous modeling and clinical analyses suggest that histamine receptor antagonists have broad prospects in the treatment of COVID-19. This article introduces the research progress of histamine H1 receptor antagonist combined with azithromycin, histamine H2 receptor antagonist famotidine alone or combined with aspirin, and histamine H1 and H2 receptor antagonists used in combination in the treatment of COVID-19. Finally, the possible mechanism of histamine receptor antagonists in the treatment of COVID-19 was introduced and the application prospect of histamine receptor antagonists in the treatment of COVID-19 was analyzed.

Drug Design and Disease Diagnosis: The Potential of Deep Learning Models in Biology

Early prediction and detection enable reduced transmission of human diseases and provide healthcare professionals ample time to make subsequent diagnoses and treatment strategies. This, in turn, aids in saving more lives and results in lower medical costs. Designing small chemical molecules to treat fatal disorders is also urgently needed to address the high death rate of these diseases worldwide. A recent analysis of published literature suggested that deep learning (DL) based models apply more potential algorithms to hybrid databases of chemical data. Considering the above, we first discussed the concept of DL architectures and their applications in drug development and diagnostics in this review. Although DL-based approaches have applications in several fields, in the following sections of the arti-cle, we focus on recent developments of DL-based techniques in biology, notably in structure predic-tion, cancer drug development, COVID infection diagnostics, and drug repurposing strategies. Each review section summarizes several cutting-edge, recently developed DL-based techniques. Additionally, we introduced the approaches presented in our group, whose prediction accuracy is relatively compara-ble with current computational models. We concluded the review by discussing the benefits and draw-backs of DL techniques and outlining the future paths for data collecting and developing efficient computational models.Copyright © 2023 Bentham Science Publishers.

Structure-Based Identification and Analysis of Viral Protease Inhibitors Targeting SARS CoV-2 Virus Replication

The re-emergence of SARS-CoV, known as SARS-CoV-2, has proven extremely infectious that has infected a huge population worldwide. SARS-CoV-2 genome is translated into polyproteins that is processed by virus-specific protease enzymes. 3CLprotease is named as the main protease (Mpro) enzyme that cleaves nsp4 to nsp16. This crucial role of Mpro makes this enzyme a prime and promising antiviral target. Till date, there is no effective commercially available drug against COVID-19 and launching a new drug into the market is a complicated and time-consuming process. Therefore, drug repurposing is a new but familiar approach to reduce the time and cost of drug discovery. We have used a high-throughput virtual screening approach to examine FDA approved library, natural compound library, and LOPAC 1280 (Library of Pharmacologically Active Compounds, Sigma-Aldrich, St. Louis, MO) library against Mpro. Primary screening identified potential drug molecules for the target, among which ten molecules were studied further using biophysical and biochemical techniques. SPR was used to validate the binding of inhibitors to purified Mpro and using FRET-based biochemical protease assay these inhibitors were confirmed to have Mpro inhibitory activity. Based on the kinetic studies, the antiviral efficacy of these compounds was further analysed by cell-culture based antiviral assays. Four out of ten molecules inhibited SARS-CoV-2 replication in Vero cells at a concentration range of 12.5 to 50 muM. The antiviral activity was evaluated by RT-PCR assay and TCID50 experiments. The co-crystallization of Mpro in complex with inhibitor for determining their structures is being carried out. Collectively, this study will provide valuable mechanistic and structural insights for development of effective antiviral therapeutics against SARS-CoV-2.

IDWeek 2022

IDWeek is the joint annual meeting of the Infectious Diseases Society of America (IDSA), Society for Healthcare Epidemiology of America (SHEA), the HIV Medicine Association (HIVMA), the Pediatric Infectious Diseases Society (PIDS) and the Society of Infectious Diseases Pharmacists (SIDP). For the first time since the COVID-19 public health emergency began, IDWeek 2022 returned to in-person attendance. It was held in Washington, D.C., and the meeting comprised 5 days of live sessions and on-demand content that included posters and oral presentations.Copyright © 2023 Clarivate.

Repurposing Drugs for the Treatment of COVID-19 and Its Cardiovascular Manifestations.

COVID-19 is an infectious disease caused by SARS-CoV-2 leading to the ongoing global pandemic. Infected patients developed a range of respiratory symptoms, including respiratory failure, as well as other extrapulmonary complications. Multiple comorbidities, including hypertension, diabetes, cardiovascular diseases, and chronic kidney diseases, are associated with the severity and increased mortality of COVID-19. SARS-CoV-2 infection also causes a range of cardiovascular complications, including myocarditis, myocardial injury, heart failure, arrhythmias, acute coronary syndrome, and venous thromboembolism. Although a variety of methods have been developed and many clinical trials have been launched for drug repositioning for COVID-19, treatments that consider cardiovascular manifestations and cardiovascular disease comorbidities specifically are limited. In this review, we summarize recent advances in drug repositioning for COVID-19, including experimental drug repositioning, high-throughput drug screening, omics data-based, and network medicine-based computational drug repositioning, with particular attention on those drug treatments that consider cardiovascular manifestations of COVID-19. We discuss prospective opportunities and potential methods for repurposing drugs to treat cardiovascular complications of COVID-19.

Drug repurposing against COVID-19 by GWAS

This note is prepared by the authors of a recent publication on shared genetic architecture of drug response based on summary statistics from genome-wide association studies (GWAS) to propose a drug repurposing approach for the treatment of coronavirus COVID-19. The authors proposed that in silico studies may be preceded by analyzing shared genetic architecture of drug response based on existing GWAS.Copyright © 2020, Health Biotechnology and Biopharma.

Safety profile assessment of drug products used for the pathogenetic treatment of COVID-19.

Objective. To review and summarize literature data in studies of safety of the drug products used for the pathogenetic treatment of COVID-19. Materials and methods. As the first stage of monitoring the drug's safety, which are used in the treatment of COVID-19 in Russia, a systematic review of studies of the drug's safety profiles was carried out: Mefloquine, hydroxychloroquine, azithromycin, lopinavir/ritonavir, favipiravir, tocilizumab, olokizumab, baricitinib in the international databases Medline, PubMed, ClinicalTrials.gov and Cochrane Library for the period 2019-2021. Results. The review included 51 articles that met the selection criteria. Based on the results of the review, it can be concluded that the safety profile (frequency, severity and severity) of most drugs repurposed for COVID-19 corresponds to those for the registered indications. At the same time, according to world experience, there is an increase in the number of reports of adverse drug reactions of hydroxychloroquine and azithromycin, which is provoked by the active use of these drugs for combination therapy. Conclusions. According to the literature, a high incidence of adverse events was noted in hydroxychloroquine, chloroquine and azithromycin. Subsequent analysis and comparison of the safety profiles of hydroxychloroquine, chloroquine and azithromycin with data from the national automated information system (AIS) database of Roszdravnadzor is a necessary component of effective and safe pharmacotherapy for COVID-19.Copyright © 2021, Interregional Association for Clinical Microbiology and Antimicrobial Chemotherapy. All rights reserved.

Drug Repositioning for Coronavirus (COVID-19) using Different Deep Learning Architectures

In December 2019, the COVID-19 epidemic was found in Wuhan, China, and soon hundreds of millions were infected. Therefore, several efforts were made to identify commercially available drugs to repurpose them against COVID-19. Inferring potential drug indications through computational drug repositioning is an efficient method. The drug repositioning problem is a top-K recommendation function that presents the most likely drugs for specific diseases based on drug and disease-related data. The accurate prediction of drug-target interactions (DTI) is very important for drug repositioning. Deep learning (DL) models were recently exploited for promising DTI prediction performance. To build deep learning models for DTI prediction, encoder-decoder architectures can be utilized. In this paper, a deep learning-based drug repositioning approach is proposed, which is composed of two experimental phases. Firstly, training and evaluating different deep learning encoder-decoder architecture models using the benchmark DAVIS Dataset. The trained deep learning models have been evaluated using two evaluation metrics;mean square error and the concordance index. Secondly, predicting antiviral drugs for Covid-19 using the trained deep learning models created during the first phase. In this phase, these models have been experimented to predict different antiviral drug lists, which then have been compared with a recently published antiviral drug list for Covid-19 using the concordance index metric. The overall experimental results of both phases showed that the most accurate three deep learning compound-encoder/protein-encoder architectures are Morgan/AAC, CNN/AAC, and CNN/CNN with best values for the mean square error, the first phase concordance index, and the second phase concordance index. © 2023,International Journal of Advanced Computer Science and Applications. All Rights Reserved.

Repurposing Approved Drugs for Sarcopenia Based on Transcriptomics Data in Humans.

Sarcopenia, characterized by age-related loss of muscle mass, strength, and decreased physical performance, is a growing public health challenge amid the rapidly ageing population. As there are no approved drugs that target sarcopenia, it has become increasingly urgent to identify promising pharmacological interventions. In this study, we conducted an integrative drug repurposing analysis utilizing three distinct approaches. Firstly, we analyzed skeletal muscle transcriptomic sequencing data in humans and mice using gene differential expression analysis, weighted gene co-expression analysis, and gene set enrichment analysis. Subsequently, we employed gene expression profile similarity assessment, hub gene expression reversal, and disease-related pathway enrichment to identify and repurpose candidate drugs, followed by the integration of findings with rank aggregation algorithms. Vorinostat, the top-ranking drug, was also validated in an in vitro study, which demonstrated its efficacy in promoting muscle fiber formation. Although still requiring further validation in animal models and human clinical trials, these results suggest a promising drug repurposing prospect in the treatment and prevention of sarcopenia.

Repurposing selective serotonin reuptake inhibitors for severity of COVID-19: A population-based study.

The World Health Organization has proposed that a search be made for alternatives to vaccines for the prevention and treatment of COVID-19, with one such alternative being selective serotonin reuptake inhibitors (SSRIs). This study thus sought to assess: the impact of previous treatment with SSRI antidepressants on the severity of COVID-19 (risk of hospitalisation, admission to an intensive care unit [ICU], and mortality), its influence on susceptibility to SARS-CoV-2 and progression to severe COVID-19. We conducted a population-based multiple case-control study in a region in the north-west of Spain. Data were sourced from electronic health records. Adjusted odds ratios (aORs) and 95%CIs were calculated using multilevel logistic regression. We collected data from a total of 86,602 subjects: 3060 cases PCR+, 26,757 non-hospitalised cases PCR+ and 56,785 controls (without PCR+). Citalopram displayed a statistically significant decrease in the risk of hospitalisation (aOR=0.70; 95% CI 0.49-0.99, p = 0.049) and progression to severe COVID-19 (aOR=0.64; 95% CI 0.43-0.96, p = 0.032). Paroxetine was associated with a statistically significant decrease in risk of mortality (aOR=0.34; 95% CI 0.12 - 0.94, p = 0.039). No class effect was observed for SSRIs overall, nor was any other effect found for the remaining SSRIs. The results of this large-scale, real-world data study indicate that, citalopram, could be a candidate drug for being repurposed as preventive treatment aimed at reducing COVID-19 patients' risk of progressing to severe stages of the disease.

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases.

Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

Docking Studies with Multiple Molecular Targets Associated with SARS-CoV-2 for Drug Repurposing

Background: The current pandemic outbreak of COVID-19 due to viral infections by SARS-CoV-2 has now become associated with severe commotion on global healthcare and the economy. Objective(s): In this extreme situation, when vaccine or effective new drugs against COVID-19 are still not available, the only quick and feasible therapeutic alternative would be the drug repurpos-ing approach. Method(s): In the present work, in silico screening of some anti-viral and antiprotozoal drugs was performed based on docking using Autodock. Result(s): Two known anti-viral drugs, sorivudine and noricumazole B, are predicted to bind to the active site of the viral proteases, namely cysteine-like protease or 3CL protease (3CLpro) and pa-pain-like protease (PLpro), respectively, with a highly favorable free energy of binding. Further, the promising molecules were subjected for checking their activity on other molecular targets in SARS-CoV-2 like spike protein S1, RNA dependent RNA polymerase (RdRp), and angiotensin converting enzyme 2 (ACE2) receptor. But the compounds were found non-effective on the rest of the molecular targets. Conclusion(s): Sorivudine alone or a combination of sorivudine and noricumazole B may be adminis-tered to impede viral replication, though the predicted drug likeliness of noricumazole B is not much satisfactory. These observations are solely based on the results from blind docking with protein molecules and need to be further corroborated with experimental results.Copyright © 2021 Bentham Science Publishers.