Throughout history, humans have endeavoured to create interventions to improve health and prevent disease. Over time, the strategies used have progressed from herbal tinctures inspired by vague theories into a dynamic, fast paced, multibilliondollar global industry. Pharmaceutical products were responsible for US$806 billion in global revenue in 2021, with Germany, Switzerland, and the United States each exporting approximately $100 billion worth [1]. The United States was the top importer of pharmaceutical products globally in 2021, bringing in a staggering $145 billion worth of products. As in any industry with such high consumer demand, there is an equally high incentive to maintain, increase, and improve supply. Unfortunately, both the monetary cost and the length of time it takes to introduce a new drug into the market are high. The average timeline from the initial idea to the commercial availability of a drug is 10-15 years. The “drug discovery pipeline”, as it is commonly called, is a long-winded and interdisciplinary process requiring chemists, biologists, doctors, and workers in many related fields. At any stage of the process, a potential drug candidate may fail during testing, resulting in the waste of both time and money. While this is an inconvenience at the best of times, during events such as the COVID-19 pandemic, it can be life threatening. When a health emergency sweeps the world, the typical timeframe of the drug discovery pipeline may be too lengthy to make a timely impact—herein lies the potential of drug repurposing.

Drug repurposing is the practice of discovering a previously unknown and unintended use for an existing drug [2]. By starting with an existing drug, investigations into a new therapeutic can be expedited significantly. When the chemical compound of interest is a current commercially available drug, it will have already passed clinical testing. This is one of the most common stages for a potential new drug to fail. Additionally, there is likely an existing understanding of the drug’s mechanism of action. In cases where the exact cause or mechanism of a disease is not known, this can offer valuable information about the possible pathophysiology of the condition. In fact, the lack of understanding of potential targets is a common reason why a drug repurposing approach may be selected to find treatments for a disease. Repurposing an existing drug also allows the practical aspect of drug design (such as how the compound can be synthesised or how it should be delivered to its target site) to proceed in less time. Finally, the process of testing existing drugs for new uses can reveal valuable insights about a drug that may have gone unnoticed during its initial testing. Unknown effects may be harmless or affect something irrelevant to the desired action, but occasionally, a new discovery may warrant extensive further research.

In collaboration with Beatrix Goggin and Jane Allison from the University of Auckland, further studies are being undertaken to better understand the effects of ADs on membranes of various compositions. This research will be aided by the use of computational molecular dynamics simulations which allow the prediction and observation of atom-level motion and interactions. It will investigate the interactions of fluvoxamine, as well as other drugs, with cell membranes of different compositions in an effort to understand the effect these drugs have on various tissue types. At the moment, initial research involves a comprehensive overview of diverse membrane types and compositions to determine the model systems that would be ideal to simulate drug interactions. This international collaboration highlights another trend in the modern drug design landscape: increased use of computational tools. Researchers from Vanderbilt University and Emory University conducted a ten-year literature review on drug repurposing for Alzheimer’s disease, which revealed that 71 of the 124 studies reviewed employed computational strategies for drug repurposing. In the first year covered by the study, 2012, zero computational studies were identified. By 2021, the penultimate year, 26 of the 44 studies reviewed contained significant computational components [9]. This increase over just a ten-year period (and only for one disease) showcases the drug design field’s participation in the exciting and rapidly evolving world of technology. Drug repurposing is an area of drug design where computational methods are particularly useful. In order to meaningfully model a system, you must have enough assumptions to build the model on. Existing drugs and some knowledge of their action on other systems are excellent starting places to investigate their effects in new, lesser known systems.

This research is just one of many examples that showcase the power and potential of drug repurposing. Early in the COVID-19 pandemic, very little was known about the method of disease spread and infection, yet solutions were desperately needed. Many drugs were appraised as a potential cure for COVID-19, including the highly publicised attempts and ultimate failures of hydroxychloroquine and ivermectin. While no single drug proved successful, each trial and study provided insight into the virus itself, in addition to new knowledge that may be helpful in the future. As well as the savings in money and time, it is also important to acknowledge the potential environmental impacts of a drug repurposing approach (especially when combined with computational methods) [10]. By starting with an existing compound, the chemical waste produced during the design and synthesis process can be avoided. Using existing drugs (and computational methods) also allows targets to be refined before screening and testing, hopefully reducing the number of trials required before a lead is identified. Overall, the surge in drug repurposing during the pandemic was a valuable reminder and needed renewal of interest in a sustainable and under-utilised approach to drug design.

A retrospective study carried out by researchers at King’s College London (KCL) revealed that during the first wave of the COVID-19 pandemic in the UK (April to December 2020), patients who received antidepressant drugs (ADs) one to three months before admission had a 40% lower incidence of COVID-19 [3]. Previous cell biology evidence had shown that ADs affect membrane trafficking, and it was hypothesised that this mechanism may underlie the prophylactic (disease-preventing) effect of ADs on COVID-19 [3]. In a 2020 publication, KCL researcher Oleg Glebov investigated how this membrane trafficking effect may specifically prevent (or decrease the severity of) SARS-CoV-2 infections.

SARS-CoV-2 enters the lung epithelium via endocytosis, a process where extracellular materials are taken into the cell by vesicles – small, fluid-filled sacs that facilitate transport through membranes [4]. Specific endocytosis pathways vary depending on cell type and what is being brought into the cell. Early in the pandemic, little was known about the particular mechanism (or mechanisms) employed by SARS-CoV-2 (some of which are shown in Figure 1), which made it difficult to target antivirals to disrupt a specific biological process [5]. With his research into repurposing ADs, Glebov hoped to shed light on the exact mechanisms of SARSCoV-2 cell entry and uncover potential treatment options for SARS-CoV-2 itself or other similar viral infections.

In addition to its impact on the pandemic, this research is also compelling because of the ubiquitous nature of the antidepressants themselves. From 2021to 2022, 8.32 million people in the UK were prescribed antidepressants [6]. Despite their widespread prescription, ADs are not well understood. The discovery of significant off-target activity is a sobering reminder of the potential extensive and damaging consequences of these unknowns.

Figure 2: The chemical structure of selective serotonin reuptake inhibitor (SSRI), fluvoxamine [8].

Figure 1: A representation of potential endocytic pathways facilitating the entrance of SARS-CoV-2 into the cell, and the potential action of drugs against the processes [5].

In his 2020 article, Glebov detailed 11 candidate ADs for future investigation into their effect on SARS-CoV-2. A subsequent publication in 2021 focused on one AD in particular, fluvoxamine, and its proven effect on SARS-CoV-2 spike protein trafficking. Using HEK293T cells expressing ACE2 receptors, subtherapeutic concentrations of fluvoxamine (Figure 2) as low as 80 nM was found to significantly upregulate fluid-phase endocytosis [7]. This resulted in the increased accumulation of the spike-ACE2 complex in enlarged early endosomes, where they may be recycled back to the outside of the cell rather than progressing to late endosomes/lysosomes and onto the replication stage of viral infection. While this research was not conducted rapidly enough to be used as a treatment during the pandemic, it provided valuable insight into the mechanism of COVID-19 infection and viral uptake into cells in general, as well as opening up a new area of research into the effects of ADs outside the central nervous system.