**Abstract**

Since the advent of the twentieth century, several severe virus outbreaks have occurred—H1N1 (1918), H2N2 (1957), H3N2 (1968), H1N1 (2009) and recently COVID-19 (2019)—all of which have posed serious challenges to public health. Therefore, rapid identification of efficacious antiviral medications is of ongoing paramount importance in combating such outbreaks. Due to the long cycle of drug development, not only in the development of a "safe" medication but also in mandated and extensive (pre)clinical trials before a drug can be safely licensed for use, it is difficult to access effective and safe novel antivirals. This is of particular importance in addressing infectious disease in appropriately short period of time to limit stress to ever more interlinked societal infrastructures; including interruptions to economic activity, supply routes as well as the immediate impact on health care. Screening approved drugs or drug candidates for antiviral activity to address emergent diseases (i.e. repurposing) provides an elegant and effective strategy to circumvent this problem. As such treatments (in the main) have already received approval for their use in humans, many of their limitations and contraindications are well known, although efficacy against new diseases must be shown in appropriate laboratory trials and clinical studies. A clear in this approach in the case of antivirals is the "relative" simplicity and a high degree of conservation of the molecular mechanisms that support viral replication—which improves the chances for a functional antiviral to inhibit replication in a related viral species. However, recent experiences have shown that while repurposing has the potential to identify such cases, great care must be taken to ensure a rigourous scientific underpinning for repurposing proposals. Here, we present a brief explanation of drug repurposing and its approaches, followed by an overview of recent viral outbreaks and associated drug development. We show how drug repurposing and combination approaches have been used in viral infectious diseases, highlighting successful cases. Special emphasis has been placed on the recent COVID-19 outbreak, and its molecular mechanisms and the role repurposing can/has play(ed) in the discovery of a treatment.

**Keywords:** viral infectious disease, COVID-19, drug development, drug repurposing, drug repurposing strategies, applications

### **1. Introduction**

The development of a new drug is an extensive, intricate, highly risky and expensive process. According to the study of 12,728 transitions over the last decade (2011–2020), the success rates of clinical drug development were 52.0% (Phase I), 28.9% (Phase II) and 57.8% (Phase III) separately [1]. Most of the candidates failed in the early drug development process for reasons of efficacy and safety concerns [2]. This causes a huge cost in drug development, ranging from tens of millions to billions. In addition, it typically takes at least 10 years from initial laboratory evaluation for a new drug to be approved. All these factors lead to low output disproportionately to the high input and make it challenging for the pharmaceutical industry to respond to emergent infectious diseases within a time frame that is able to impact the course of an outbreak. As a result, the development of vaccine candidates will likely remain to be the optimal mechanism to address outbreaks in the immediate future. Notwithstanding the extraordinary developments in vaccine technology exemplified by recent events [3, 4]—there still remains a need for therapeutics as a sufficiently successful virus will rapidly become pan/endemic, creating a constant need for treatment of those unfortunate enough to not have access to a vaccine due to socioeconomic, age or immunostatus issues. Indeed, in the case of a pandemic, there is likely to be constant strain on health systems to treat patients, which will significantly enhanced in the absence of an effective therapy as it will instead rely heavily on patient support technologies such as ventilation or oxygen therapy.

A potential solution to this conundrum is the examination of already proposed (ideally approved) medications—repurposing—to assess their potential in the treatment of an emergent diseases. Drug repurposing as a strategy to identify potential new indication areas of approved/old drugs has many advantages. Firstly, low risk. Most repurposed drugs have at least been tested in early clinical trials. Hence, the failure rate of repurposing candidates caused by safety is very low. Secondly, low cost. Most old or approved drugs have clear safety, pharmacokinetics and pharmacodynamics data, which reduces the studies that need to be performed before the drugs extension to a novel indication. Thirdly, a higher success rate. The drugs used for repurposing are enriched from previous studies. This means less promising compounds are filtered out, allowing for a higher success rate [5]. Finally, while the molecular complexity of the protein targets of diseases is extremely broad, areas of essential molecular function can be identified as conserved in many diseases. For example, tyrosine kinase activity is a frequent target for the development of cancers from highly diverse tissues. A common feature of all kinases is the presence of an ATP-binding site, which has resulted in a large number of targeted cancer therapies (tyrosine kinase inhibitors, TKIs) which have a strong resemblance to ATP on the molecular level. This has further resulted in the clinical testing of TKIs for cancers distinct to those for which they were developed, as the evolutionary pressure to retain a function ATP-binding site provides a precondition for potential TKI cross-reactivity [6].

In the past decades, the successful application of drug repurposing shows a promising direction for drug development. For example, Thalidomide was firstly synthesized by Ciba in 1953 and came on to the market to relieve morning sickness in 1957. In 1961, Thalidomide was taken off the market due to the severe teratogenic effect on the developing fetus. In the following years, an Israeli researcher found that thalidomide could be used as a treatment against autoimmune diseases. In 1998 it was approved by FDA for the repurposed use in the treatment of ENL [7–9]. In this chapter, we present an overview of the benefits and drawbacks of drug repurposing in viral disease, including approaches, applications and outlook.

### **2. Drug repurposing**

Drug repurposing is the process of identifying new indications and uses for approved/existing drugs [10]. It mostly involves approved drugs or compounds

### *Drug Repurposing Techniques in Viral Diseases DOI: http://dx.doi.org/10.5772/intechopen.101443*

under study, which have clear pharmacokinetics and pharmacodynamics that provide data on metabolic stability, tissue distribution and clearance rates. In the past decades, a large quantity of new molecular entity drugs was approved or studied, meaning that not only the ~2000 FDA approved compounds can be screened [11, 12], but also a much larger potential library of compounds that have been developed to have appropriate physico-chemical properties for their use as drugs, but that may have failed clinical trials due to lack of action in their original disease class. This, perhaps, is the key benefit of repurposing—as all potential repurposing candidates possess "drug-like" properties. However, these properties should be borne in mind by the researcher as they strongly impact the potential of repurposed compounds in clinical use.

The classic description of "drug-like" properties has grown significantly since the original introduction of the "Rule of 5" by Lipinski (Ro5) [13]. This initial classification arose from the observation that successful drugs shared common properties: low molecular weight (Mw), a relative scarcity of potential electrostatic interactions (H-bond donors and acceptors) and a partition coefficient (logP) that indicated the molecules would be able to passively diffuse across cell membranes. While, the most important descriptors remain unchanged a summary of Lipinski's and others rules is provided in **Table 1** [13–17]. As repurposing candidates will be drawn from compounds that are likely to be enriched for these properties and therefore the potential route of administration for the repurposed disease should be compatible with these. For instance, compounds that are a good fit to Ro5 would be relatively poorly applied to diseases for which administration would be via inhalation [18]. Thus, the availability of this pharmacological information and likely route of administration is of key importance in deciding on which compounds should be assessed for repurposing.

In summary, these studies provide a wealth of information about the clinical application and mechanism of action, aiding the rapid development of the drug repurposing. When compared with *de novo* drug discovery, drug repurposing accelerates the development process and significantly reduces development risk [19].
