Introduction to Drug Repurposing: Exploring New Applications for Existing Drugs

Abstract

This chapter delves into the concept of drug repurposing, which involves identifying new therapeutic applications for existing drugs. Drug repurposing offers a cost-effective and time-efficient approach to drug discovery by leveraging the knowledge and safety profiles of approved or investigational drugs. The chapter provides an overview of the principles and strategies employed in drug repurposing, including high-throughput screening, repurposing based on mechanistic insights, computational methods, and the increasing role of artificial intelligence in drug repurposing, as this is an emerging trend in the field. It explores successful case studies where repurposed drugs have shown promise in treating different diseases. Furthermore, the chapter discusses the challenges and opportunities associated with drug repurposing, including regulatory considerations and intellectual property issues. Overall, this chapter serves as a valuable resource for researchers and professionals in the field of drug development, emphasizing the potential of repurposing existing drugs to address unmet medical needs.

1. Introduction

Traditional drug discovery has long been a laborious and costly process, often taking years or even decades to bring a new drug to market [1]. The journey from initial target identification to clinical approval involves a high failure rate due to issues such as poor efficacy, toxicity, and unforeseen side effects [2]. These challenges have led to soaring research and development costs, making drug development increasingly unaffordable for both pharmaceutical companies and patients [3]. As a result, there is a pressing need for innovative approaches that can expedite the drug development process and increase the chances of success [4].

Drug repurposing, also known as drug repositioning or reprofiling, emerges as a promising solution to this dilemma [5]. It involves identifying new therapeutic applications for existing drugs that have already been approved for other indications or are currently undergoing investigation in clinical trials [6]. By building upon the extensive knowledge and safety profiles of these drugs, researchers can bypass several stages of preclinical testing and early clinical trials, significantly reducing both time and expenses [6].

The rationale behind drug repurposing lies in the vast reservoir of information surrounding approved drugs, including their pharmacokinetics, pharmacodynamics, and adverse event profiles [7]. These attributes offer valuable insights into how the drugs interact with the human body, their potential off-target effects, and established dosing regimens. Leveraging this information can accelerate the process of identifying new therapeutic targets and understanding the mechanisms of action, making drug repurposing a promising strategy to address unmet medical needs effectively [8].

Moreover, drug repurposing is not only advantageous for its cost-effectiveness but also for its potential to bring new treatments to patients more rapidly. It opens avenues to explore alternative therapeutic indications and expand the utility of drugs beyond their original purpose [5, 8]. As the field of drug repurposing advances, it has the potential to revolutionize the drug development landscape, offering hope for patients with limited treatment options and encouraging pharmaceutical companies to invest in areas where repurposing opportunities exist [6].

In this chapter, we delve into the principles, strategies, and success stories of drug repurposing. We explore various computational methods, high-throughput screening techniques, and mechanistic insights that drive successful drug repurposing endeavors. Additionally, we discuss the challenges and opportunities associated with this approach, ranging from regulatory considerations and intellectual property issues to funding and investment challenges. By offering a comprehensive overview of drug repurposing, this chapter aims to provide a valuable resource for researchers and professionals in the field of drug development, emphasizing the immense potential of repurposing existing drugs to address unmet medical needs.

1.1 Advantages of drug repurposing over traditional drug discovery

Drug repurposing offers several compelling advantages over the traditional drug discovery process, making it an attractive approach for addressing the challenges faced in bringing new therapeutics to market [9].

One of the most significant advantages of drug repurposing is its cost-effectiveness and time efficiency [8]. Traditional drug discovery from scratch can take up to 10–15 years and cost billions of dollars [1, 3]. In contrast, repurposing existing drugs significantly reduces the time required for drug development. By starting with compounds that have already undergone safety testing and optimization, researchers can skip the early stages of preclinical development, thereby shortening the overall timeline for getting a drug to the market. Additionally, repurposing minimizes the costs associated with preclinical and phase I clinical trials, making it a more financially viable option, especially for academic institutions and smaller pharmaceutical companies with limited resources [10, 11].

Another key advantage of drug repurposing is the access to extensive safety profiles and clinical data of already approved drugs [12]. For drugs that have been used for years or decades, there is a wealth of information available on their pharmacokinetics, pharmacodynamics, adverse events, and interactions with other drugs [13]. This knowledge significantly reduces the uncertainty associated with drug safety, streamlining the regulatory approval process. Leveraging existing clinical data also allows researchers to identify potential adverse effects and contraindications early in the drug development journey, improving patient safety and reducing the risk of unexpected side effects [14].

Repurposed drugs may also have well-established dosing regimens and formulations, which can further expedite their entry into the market [15]. By building upon this existing foundation, drug repurposing endeavors can focus more on targeted research and development, leading to quicker translation of discoveries into clinical applications. So, drug repurposing represents a compelling alternative to traditional drug discovery, offering cost-effectiveness, time efficiency, and access to well-characterized safety profiles [12]. By capitalizing on the extensive knowledge and experience of existing drugs, drug repurposing opens new opportunities to address unmet medical needs, providing hope for patients and a pathway to overcome the challenges posed by the high costs and time-intensive nature of traditional drug development [16, 17].

2. Principles of drug repurposing

The principles of drug repurposing revolve around utilizing existing drug knowledge, employing advanced data analysis tools, identifying potential therapeutic targets, and gaining mechanistic insights [18]. By harnessing the power of existing drugs and comprehensive data analyses, drug repurposing offers a strategic and efficient approach to discovering new therapeutic applications for the benefit of patients and healthcare systems alike [17, 19].

2.1 Utilizing knowledge and safety profiles of existing drugs

Existing drugs offer a wealth of valuable data that can significantly expedite the drug repurposing process [20]. These drugs have often undergone extensive preclinical and clinical testing, providing researchers with well-documented information on their pharmacokinetics, pharmacodynamics, and safety profiles [21]. By leveraging this existing knowledge, researchers can gain insights into how these drugs interact with the human body, their specific mechanisms of action, and potential off-target effects [22]. Drug repurposing efforts heavily rely on drug databases and advanced bioinformatics tools [23]. These databases aggregate information from various sources, such as clinical trials, electronic health records, and published literature, providing researchers with a comprehensive overview of drug-drug interactions, side effects, and disease associations [21, 23]. Bioinformatics tools enable researchers to identify potential therapeutic targets and predict drug-repurposing candidates by analyzing biological data, molecular structures, and computational models [24].

2.2 Identifying potential therapeutic targets for repurposing

Target identification is a crucial step in drug repurposing, aiming to uncover potential therapeutic uses for existing drugs beyond their original indications. Researchers employ various methods to identify suitable targets, focusing on disease mechanisms and common pathways [25].

Target identification methods encompass a range of approaches, including genetic studies, omics technologies (genomics, proteomics, metabolomics), and systems biology analyses [26, 27]. These methods allow researchers to unravel the molecular underpinnings of diseases, pinpoint dysfunctional genes or proteins, and identify key signaling pathways that could be modulated by repurposed drugs [28]. The success of drug repurposing often relies on understanding the underlying disease mechanisms and common molecular pathways shared by multiple diseases [28]. By identifying these shared pathways, researchers can identify drugs that have the potential to affect multiple disease conditions, broadening the scope of therapeutic applications [26].

2.3 Understanding mechanistic insights for repurposing

Mechanistic insights play a vital role in drug repurposing, guiding researchers in selecting suitable drugs and optimizing their application for new therapeutic indications [29]. Off-target effects refer to the interactions between drugs and biological targets other than the intended target. In drug repurposing, off-target effects can be both a challenge and an opportunity [30]. Understanding the off-target effects of a drug can help researchers identify additional therapeutic indications, expanding the drug’s potential uses beyond its primary target [31]. Case studies are essential in illustrating the mechanistic insights gained through drug repurposing endeavors. These real-life examples highlight how drug candidates, originally developed for one condition, were successfully repurposed for other diseases based on their specific mechanisms of action and pharmacological properties [32]. These case studies provide valuable evidence and support for the feasibility and efficacy of drug repurposing.

3. Strategies for drug repurposing

3.1 Computational methods and in silico approaches

Computational methods play a crucial role in drug repurposing by enabling researchers to analyze vast databases of drugs and potential targets efficiently [33]. Virtual screening involves the use of computer algorithms to identify candidate drugs that have the potential to bind to a specific target of interest [18, 34]. Molecular docking, a common virtual screening technique, predicts the binding mode and affinity between a drug molecule and a target protein, providing insights into their interactions at the molecular level [35]. By virtually screening thousands of compounds against a target of interest, researchers can prioritize the most promising candidates for further investigation, significantly reducing the number of compounds that need to be experimentally tested [35]. Computational data analysis allows researchers to integrate information from diverse sources, such as drug databases, protein structures, and genetic data, to prioritize repurposing candidates [36]. Through machine learning algorithms and network analyses, researchers can identify potential drug-target interactions and predict the efficacy of drug candidates for different diseases [37]. Computational data-driven drug prioritization helps researchers focus their experimental efforts on the most likely candidates, leading to more efficient and targeted drug repurposing projects [38].

3.2 High-throughput screening techniques

High-throughput screening (HTS) is a powerful experimental technique that allows researchers to test thousands of compounds simultaneously for their activity against a specific biological target [39]. In drug repurposing, HTS can be employed to identify potential drug candidates that exhibit activity against a new target or disease [40]. By screening approved drugs or investigational compounds against a panel of disease-relevant targets, researchers can identify hits that show promise for further development [41].

3.3 Structure–activity relationship (SAR) analysis

Structure–activity relationship (SAR) analysis is a fundamental concept in drug discovery and development [42]. It involves studying how the chemical structure of a drug molecule influences its biological activity, such as its binding to a specific receptor or enzyme, and its subsequent pharmacological effects. By understanding SAR, researchers can gain insights into the molecular interactions that govern a drug’s efficacy, potency, selectivity, and safety profile. In the context of drug repurposing, SAR analysis becomes particularly valuable [43]. Drug repurposing, also known as drug repositioning or reprofiling, refers to the process of identifying new therapeutic uses for existing drugs that were originally developed for a different medical indication [22]. This approach offers several advantages over traditional drug development, such as reduced costs, shorter development timelines, and access to a wealth of safety and pharmacokinetic data [12]. When exploring drug repurposing opportunities, researchers can leverage the knowledge gained from SAR analysis of approved drugs to identify potential candidates for new indications [44]. By identifying the critical structural features responsible for the activity against a known target, researchers can predict whether a drug may have similar interactions with a different biological target, leading to a therapeutic effect in a distinct disease context [43]. The process of SAR analysis involves synthesizing and testing structurally related analogs or derivatives of a known drug to evaluate how modifications impact its activity. These modifications can include adding or substituting functional groups, altering the core scaffold, or changing the stereochemistry [45]. Through iterative testing, researchers can determine the key structural elements responsible for a drug’s activity and optimize its potency and selectivity against the desired target. Moreover, SAR analysis can help identify potential off-target effects and predict potential adverse reactions, contributing to a better understanding of a drug’s overall safety profile [42]. This is especially relevant in drug repurposing, as existing drugs have already undergone significant preclinical and clinical testing, providing a wealth of safety data that can inform the decision-making process. Machine learning and computational approaches have also been employed to aid in SAR analysis [46]. By analyzing large datasets of chemical structures and biological activities, these methods can identify patterns and relationships that might not be immediately apparent through traditional experimentation.

So, SAR analysis plays a crucial role in drug repurposing efforts by providing a rational framework for identifying and optimizing drugs for new therapeutic applications. By leveraging existing knowledge of approved drugs, researchers can expedite the drug development process, potentially leading to the discovery of novel treatments for a wide range of medical conditions.

4. Examples of successful drug repurposing

Drug repurposing has proven to be a valuable strategy in medicine, providing opportunities to identify new therapeutic uses for existing drugs and expedite the development of treatments for various conditions. The examples mentioned below demonstrate how drug repurposing (Figure 1) can lead to significant advancements in medical care and patient outcomes across different areas of healthcare, including infectious diseases, cancer therapy, and neurological disorders.

Figure 1.

List of some repurposed drugs.

4.1 Aspirin

The history of aspirin exemplifies successful drug repositioning. Originally marketed as an analgesic in 1899, it was later repurposed as an antiplatelet drug in the 1980s, leading to its widespread use for preventing cardiovascular events. Aspirin’s mechanisms of action involve selective inhibition of cyclooxygenase enzymes at different doses. Ongoing research suggests a potential new repositioning of aspirin in oncology, as it has been shown to reduce the risk of developing certain cancers, including colorectal cancer, through COX-2 inhibition. However, challenges related to intellectual property issues might deter further exploration by the pharmaceutical industry in this area. Nonetheless, the history of aspirin demonstrates the importance and potential of drug repositioning in providing new therapeutic opportunities for existing medications [47].

4.2 Ebselen

Ebselen, also known as PZ-51, DR3305, and SPI-1005, is a selenorganic drug with peroxynitrite and hydroperoxide activities. It has been reported to possess cytoprotective, anti-bacterial, antioxidant, and anti-inflammatory properties, as well as acting as an apoptosis inducer and a free-radical scavenger, making it a neuroprotective agent. Ebselen has been used in the treatment of noise-induced hearing loss and bipolar mood disorder. Recent studies have shown promising antiviral activity against SARS-CoV-2, with ebselen identified as a main and papain-like protease inhibitor. It is currently undergoing phase 2 clinical trials for COVID-19 treatment. However, further research, including in vivo studies and randomized clinical trials, is needed to establish its efficacy fully [48].

4.3 Thalidomide

Thalidomide, known for its tragic history of teratogenicity, was banned by the WHO in 1962 due to its harmful effects on developing fetuses. However, in 1964, Dr. Jacob Sheskin discovered its remarkable efficacy against erythema nodosum leprosum, an autoimmune complication of leprosy, which led to its repositioning by Celgene in 1998 for leprosy complications. Thalidomide’s use in such cases requires stringent contraceptive measures to prevent exposure during pregnancy. In a second repositioning, thalidomide showed promise in oncology. Investigations into its teratogenic mechanism revealed its antiangiogenic activity, which inhibits blood vessel formation. This property prompted research into its potential use to block or destroy blood vessels supplying malignant tumors. In 2006, it was successfully repositioned as a first-line treatment for multiple myeloma, marking a significant advancement in its therapeutic applications [47].

4.4 Dexamethasone

Dexamethasone is a corticosteroid that was repurposed for the treatment of severe COVID-19 cases. Initially used for various inflammatory and immunosuppressive conditions, including asthma and rheumatoid arthritis, it was evaluated in clinical trials during the COVID-19 pandemic. The RECOVERY trial, conducted in the United Kingdom, demonstrated that dexamethasone reduced mortality in hospitalized COVID-19 patients requiring respiratory support, such as those on mechanical ventilation or oxygen therapy. This drug works by dampening the immune system’s overreaction to the virus, particularly the cytokine storm that occurs in severe COVID-19 cases [49, 50].

5. Challenges and opportunities in drug repurposing

Drug repurposing offers significant opportunities for finding new therapeutic uses for existing drugs, but it also comes with its unique set of challenges. Despite these challenges, drug repurposing presents valuable opportunities for expanding treatment options, addressing unmet medical needs, and accelerating the drug development process. Overcoming these challenges requires innovative funding models, strong collaborations, and regulatory support to incentivize further exploration of drug repurposing potential [32].

Some of the key challenges and opportunities in drug repurposing are summarized in the inset of Figure 2.

Figure 2.

Some of the key challenges and opportunities in drug repurposing.

5.1 Challenges

5.1.1 Limited funding for repurposing research

Drug repurposing may not attract as much funding as the development of new drugs, especially from private investors who often seek novel and exclusive products [32].

5.1.2 Lack of incentives for pharmaceutical companies

Pharmaceutical companies may be hesitant to invest in repurposing research due to limited opportunities for patent protection and market exclusivity, which affects potential revenue streams [4].

5.1.3 Identifying new indications

Finding suitable new therapeutic uses for existing drugs requires comprehensive knowledge of the drug’s pharmacology and disease mechanisms, which can be complex and time-consuming [32].

5.1.4 Regulatory challenges

Repurposing may involve using drugs for conditions outside their original approval, leading to additional regulatory requirements and uncertainties [32].

5.1.5 Clinical trials complexity

Conducting clinical trials for drug repurposing can be challenging, especially when the original drug has a well-established safety profile, and determining appropriate dosages and patient populations can be complex [4].

5.2 Opportunities

5.2.1 Accelerated development timeline

Drug repurposing can significantly reduce drug development timelines compared with starting from scratch with new chemical entities [4].

5.2.2 Existing safety data

Repurposed drugs benefit from extensive safety data gathered during their previous use, reducing the need for extensive safety testing [32].

5.2.3 Cost-efficiency

Drug repurposing can be more cost-effective than developing new drugs, as it bypasses many of the early-stage research and preclinical testing expenses [51].

5.2.4 Rare and neglected diseases

Repurposing can provide potential treatments for rare and neglected diseases, as it leverages existing drugs that might not otherwise undergo development [52].

5.2.5 Combination therapies

Repurposed drugs can be combined with existing therapies, enhancing treatment options for various medical conditions [17].

6. Conclusion

This chapter underscores the significance of drug repurposing as a pivotal strategy in contemporary drug discovery. By identifying novel therapeutic applications for established drugs, this approach offers an efficient and cost-effective route to addressing unmet medical needs. Leveraging the wealth of knowledge and safety data associated with approved or investigational drugs, drug repurposing streamlines the development process. The chapter’s comprehensive exploration of principles and strategies, spanning computational methods, high-throughput screening, and mechanistic insights, illustrates the multifaceted nature of this approach. Through illuminating case studies, it becomes evident that repurposed drugs hold substantial promise in the treatment of diverse diseases. In recognizing both the challenges and opportunities inherent in drug repurposing, including regulatory and intellectual property considerations, the chapter provides a holistic view of this dynamic field. To summarize, this chapter stands as an invaluable resource, poised to guide researchers and professionals within the realm of drug development, catalyzing the realization of repurposed drugs’ potential in meeting pressing medical demands.

7. Future perspective

Looking forward, the landscape of drug repurposing is poised for a series of dynamic and transformative shifts that have the potential to reshape the entire paradigm of drug development and therapeutic innovation. At the forefront of this evolution is the concept of precision medicine, which is anticipated to drive a new era of tailored repurposing strategies. With the advancement of cutting-edge technologies such as single-cell genomics and high-resolution imaging, researchers are poised to delve deeper into the intricate molecular and cellular nuances of diseases. This deeper understanding is expected to pave the way for the selection and repurposing of drugs that are precisely attuned to the unique molecular profiles of specific patient subgroups, ushering in a level of therapeutic precision previously unattainable. Moreover, the future of drug repurposing will see the convergence of multiple disciplines, with network pharmacology and the concept of synthetic lethality emerging as pivotal factors. Network pharmacology, which focuses on the intricate interactions within biological systems, promises to illuminate previously undiscovered drug targets and potential repurposing opportunities. Concurrently, the identification of synthetic lethality, where the combination of two drugs proves lethal to a particular target, could revolutionize the approach to drug repurposing by opening new avenues for the exploration of synergistic drug combinations. The scope of drug repurposing is also expected to expand beyond traditional small-molecule drugs, encompassing biologics as well. This transition is driven by the growing realization of the therapeutic potential harbored within biological drugs, including monoclonal antibodies. Repurposing biologics could unlock novel ways to address complex diseases such as cancer and autoimmune disorders, offering fresh avenues for therapeutic intervention. Crucially, the integration of artificial intelligence (AI) and machine learning into the drug repurposing landscape is anticipated to be a game-changer. These advanced algorithms are uniquely poised to rapidly sift through and analyze vast and complex datasets, predicting potential drug-disease associations, and optimizing drug combinations for enhanced synergistic effects. The resultant acceleration in data-driven insights has the potential to significantly expedite the identification of repurposed drug candidates, facilitating faster and more informed decision-making in the repurposing process. As drug repurposing continues to gain prominence on the global stage, collaboration is expected to emerge as a hallmark of future endeavors. Collaboration between researchers, pharmaceutical companies, regulatory agencies, and public health organizations is projected to accelerate the identification, validation, and deployment of repurposed drugs, particularly in response to pressing global health challenges and emergencies [53, 54].

Acknowledgments

All the authors greatly acknowledge the Department of Chemistry, University of Swabi, Khyber Pakhtunkhwa, Pakistan.

Conflict of interests

The authors declared no conflict of interest.