Drug Repurposing for Antivirals

Multiple deaths result from infections caused by viruses worldwide. In recent years the world has experienced multiple outbreaks of viral diseases that were once considered harmless. These diseases have been ignored for a long time, and there are no approved medications or vaccinations, leaving the pharmaceutical industry and various research groups running out of time to find new therapies or prevention strategies. Developing new antiviral compounds costs $350 million to $2 billion, and it takes 10-15 years for the compound to transition from medical labs to clinics worldwide. Increased interest in medication repurposing methods has emerged to address these shortcomings. New drug repurposing strategies have significantly reduced the rate of failure, which was previously around 92%. Since it uses safe pharmaceuticals, medication repurposing is rapid and cost-effective. This chapter focuses on recent developments in identifying broad-spectrum antiviral drugs through repurposing existing medications. It was determined that there are two basic groups of repurposed antivirals: direct-acting antivirals (DARA) and host-targeting antivirals (HTRA). Specific categories were used to highlight a variety of approaches to repurposing medications for the treatment of viral infectious diseases such as Ebola, ZIKA, dengue, influenza, HIV, HSV, and CMV, amongst others. Drug repurposing is a promising way to generate novel antiviral drugs swiftly for addressing challenges in antiviral treatment, and it is one of the most efficient methods that can be used. The outcomes of pharmacological repurposing that present the most favorable outcomes for the treatment of infectious diseases are presented in this chapter.

The incessant emergence of novel viral pathogens poses a perpetual challenge to global public health. Traditional drug development pipelines often lag behind the urgent need for effective antiviral treatments. In this context, drug repurposing has emerged as a promising strategy to expedite the identification and deployment of therapeutics against both known and novel viral infections. This article explores the concept of drug repurposing in antiviral therapy, highlighting its potential to harness existing pharmaceutical agents for novel indications. By leveraging the extensive knowledge of drug safety profiles, pharmacokinetics, and mechanisms of action, repurposed drugs offer a shortcut to clinical trials and regulatory approval, thereby accelerating the time to market. Furthermore, drug repurposing provides a cost-effective approach compared to de novo drug discovery and development. This article reviews successful examples of drug repurposing in antiviral therapy, such as the use of nucleoside analogs originally developed for other viral infections like HIV and hepatitis C, now being repurposed for emerging viral threats such as SARS-CoV-2. Additionally, it discusses the challenges and limitations associated with drug repurposing, including issues related to intellectual property, off-label use, and the need for robust preclinical and clinical evidence. Overall, drug repurposing presents a compelling avenue for the rapid response to emerging viral outbreaks, offering a pragmatic and resource-efficient approach to combat the evolving landscape of infectious diseases.

The ongoing challenges in antiviral drug development, exacerbated by the emergence of novel viruses and the need for rapid therapeutic solutions, have led to a growing interest in drug repurposing strategies. This chapter explores the dynamic landscape of drug repurposing in antiviral therapy, focusing on the synergistic integration of in-silico and target-based approaches. The chapter begins with an introduction to the significance of drug repurposing in overcoming traditional drug development hurdles. It delves into in-silico approaches, elucidating the role of computational methods, molecular docking, and bioinformatics tools in identifying potential repurposed drugs. Simultaneously, the chapter investigates target-based approaches, highlighting the importance of target identification, validation, and screening strategies. Emphasizing the transformative potential of integrating in-silico and target-based methods, the chapter explores how combined approaches enhance the efficiency and accuracy of drug repurposing. Challenges, such as ethical considerations, data quality, and regulatory hurdles, are addressed, providing a comprehensive overview of the field's complexities. Future perspectives, including the role of emerging technologies and personalized antiviral therapies, are discussed to guide further research. The chapter concludes with a detailed analysis of case studies, focusing on successful examples like Remdesivir and other notable instances, offering valuable insights and lessons for the future of antiviral drug repurposing. This comprehensive exploration contributes to the evolving landscape of drug development, providing a roadmap for researchers and clinicians engaged in the critical endeavour of combating viral infections through innovative and efficient therapeutic strategies.

 Emerging viral and re-emerging epidemic viral infectious diseases continued by global commerce, travel, and ecological system alteration are of public health concern. Despite concerted efforts and successful vaccination in limiting viral infections, humans are still terribly losing the battle against the microbes. Persisting pandemics, acquisition of drug resistance, and emerging and re-emerging microbes impose challenges and add substantial time and costs to develop broad-spectrum antivirals, which ultimately leads to prolonged hospital stays and doctor visits and increases global mortality. In this regard, drug repurposing is a great way to find new applications for already-approved therapies that circumvent numerous time-consuming experiments as well as financial costs associated with novel drug development. Screening of drugs directly using animals or via in-vivo method is challenging, timeconsuming, and expensive, which limits the assessment and re-use of already available drugs for repurposing. In-vitro drug testing is a vital stage in the drug discovery process and also reduces animal usage. To date, several in-vitro approaches are in use for the screening of new anti-viral agents and already approved strategies for drug repurposing. In-vitro anti-viral testing of compounds or any available market drug can assess the potential effectiveness in the pre-clinical model of anti-infective and deliver imperative information to determine the best combination ratios and dosing schedule. This chapter summarizes different traditional as well as modern in-vitro (biochemical and cell-based a) methods viz. TCID50, EC50 /CC50, Plaque, HAI assays (hemagglutination inhibition), ELISA/Luminex, Plaque-Reduction Neutralization Tests (PRNTs), plaque assays, or RT-PCR analysis, cytopathic effect (CPE)-based drug screening, and a high-throughput, high-content Automated Plaque Reduction (APR) used for the repurposing of drugs as anti-viral agents. Additionally, the chapter will provide the shortcomings, advantages and challenges of these modern and traditional methods. Information regarding the plant extracts, their active constituents, available marketed drugs, and compounds from different sources, which were remedies for different pathologies and were repurposed as anti-virals by using these methods, is also compiled.

In-vivo models or animal-based evaluation of any new chemical/ natural entity is a necessary stage of the drug development process. To validate the realistic efficacy of an in-vitro lead for clinical use, pre-clinical animal models are widely used and also form regulatory requirements in the licensing process, as in-vitro experiments only provide a potential extracellular drug concentration. However, thorough investigations using in-vivo models give more details regarding free as well as unbound drug concentrations present in interstitial fluid. Translation of already approved drugs for new and emerging viral diseases through repurposing can be a time-reducing, costeffective, and sustainable process as compared to finding a new drug. Considering the complex interaction of infective agents with the host immune and neuroendocrine system, the selection of an appropriate animal model is crucial for getting the pertinent, and precise translatable data. For drugs that have already been approved by the FDA, in-vivo drug dose and exposure period along with pharmacokinetics data, are generally known for a disease. This an be utilized to assess a drug's potential usefulness in treating novel viral indications. Despite of this, anti-infective animal models are primarily limited to the screening of anti-viral monotherapy and are not substantially employed for combinational chemotherapies. Here, this chapter summarizes the different animal and in-vivo models that are in use for screening as well as the repurposing of drugs for their anti-viral efficacy against numerous emerging and reemerging fatal viral diseases.

Furthermore, the chapter will also provide information regarding the pros and cons of different in-use in-vivo models for various viral infections, including diseases of global public health concern.

Recent advancements in artificial intelligence have made strides in all aspects of human life. The drug development process has enhanced significantly, especially during the COVID-19 period. AI has made the in-silico methods even faster and more accurate, which are now more capable of guiding the initial stages of drug discovery. AI-based protein structure prediction has made it possible to avail the dynamic structure 3D of proteins, which is not possible through crystallography or other wet lab techniques. Advanced AI algorithms are being developed to cater to the specific characteristics of ligands, proteins, and different steps of drug development. With time, more relevant data are becoming available, which will improve AI-based experiments even further. This chapter has enlisted computational methods used with AI and how they differ from the traditional physics-based approaches. Under this framework, the chapter aims to gain insight into the primary research on drug repurposing for application in the treatment of viral infection using AI and ML techniques. Suramin, a polyanionic sulfonate antiparasitic drug, showed potential antiviral activities in the Zika virus (ZIKV) infection. Likewise, Sofosbuvir, a viral protease inhibitor primarily used for anti-hepatitis C virus infection, can be reused as a prophylactic treatment in SARS-CoV-2.

New viruses are always emerging, endangering global health systems. Uncontrolled epidemics have the potential to develop into pandemics that severely impact our healthcare and financial infrastructures as we have faced COVID-19. Viral illnesses kill millions of people worldwide each year. There are several limitations and problems with the antiviral treatment that need to be fixed right away. These include resistance situations, increased dosage and frequency of administration, bioavailability problems, non-specificity, etc. The advancement of nanomedicine could aid in overcoming these challenges. To reduce the previously described adverse effects of antiviral treatment, current research emphasizes the need for a greater understanding of the potential and precise application of diverse lipid, polymer, nanoparticles, and elemental-based nanoformulations. Since there is presently no globally approved treatment for viral infection, which contributes to the rapid spread of viruses and the growing need for prompt action, drug repurposing has emerged as one of the primary strategies in the battle against viral infection. Repurposed drugs are currently being tried against viral infection to control hyper-inflammation and an overreaction to the immune system in cases of severe sickness or to address the replication and spread of the virus. Nanotechnology may be able to address several issues with traditional antiviral therapies. For example, the pharmacokinetic profile of antiviral drugs can be greatly enhanced while reducing their systemic toxicity by employing nano-delivery vehicles. Another unique nanomaterial's virucidal or virus-neutralizing properties may be put to use.

Emerging or re-emerging viruses are still major threats to public health. Prophylactic vaccines represent the most effective way to prevent viral infections. However, antiviral therapies are more promising for those viruses against which vaccines are not effective enough or contemporarily unavailable. The emergence of repurposed drugs for antiviral therapy has gained significant attention in recent years due to their potential to offer cost-effective solutions amidst the ongoing challenges posed by emerging and re-emerging viral infections. This book chapter provides a comprehensive analysis of the pharmacoeconomics surrounding the repurposing of drugs for antiviral therapy. It examines the economic implications of repurposed drugs compared to traditional drug development approaches, considering factors including development costs, time-to-market, regulatory pathways, cost-effectiveness, etc. Furthermore, the chapter explores the impact of repurposed antiviral drugs on healthcare systems, highlighting their potential to mitigate the economic burden associated with viral outbreaks. Finally, we discuss potential avenues for further investigation in drug repurposing efforts.

Recent times have witnessed an urgent need for effective antiviral therapies, especially after the COVID-19 pandemic. Traditional drug discovery processes are often time-consuming and resource-intensive, prompting the exploration of alternative approaches like drug repurposing. This chapter aims to provide insights into the potential of drug repurposing as a viable strategy for combating viral infections and improving public health outcomes. Drug repurposing involves investigating existing drugs, already approved for one indication, for their therapeutic potential against other diseases, including viral infections. This approach offers several advantages, such as reduced cost and time for clinical application, as repurposed drugs have already undergone rigorous safety and pharmacokinetic evaluations. Zidovudine, molnupiravir, and remdesivir are some of the examples of the successful repurposed drugs that have demonstrated efficacy against various viral infections. However, there are instances where repurposed drugs have not shown significant therapeutic benefit, as in the case of hydroxychloroquine for managing COVID-19. Recent technological advancements, such as artificial intelligence and computational biology, could revolutionize drug repurposing for antiviral therapies. However, identifying potential drug candidates for repurposed antiviral therapy, its safety, efficacy, and clinical outcome remains a challenge.

The new beta coronavirus responsible for the current COVID19 pandemic had started to spread among people towards the end of 2019. Unmatched global searches were conducted to identify and reuse antiviral drugs from lists of approved drugs and recognised bioactive compounds. Antiviral drug development standards were rapidly circumvented, which often led to unsatisfactory results. The main drawbacks of this technique include promiscuous or cytotoxic compounds resulting in false positives. Several articles, press announcements, and media posts misled readers and occasionally diverted important attention from the search for reusable drugs. Funding for clinical trials with a low possibility of success, the empirical identification of factors that mitigate clinical indicators—such as the development of better disease management through immunomodulators and promiscuous/cytotoxic substances that cause inaccurate results—has led to breakthroughs in the clinic instead of in the lab.