Drug Repurposing: Challenges and Successes in the Treatment of SARS-CoV-2

Abstract

The coronavirus disease 2019 (COVID-19) outbreak resulted in an economic burden, with millions of morbidity and mortality infections, due to the unavailability of treatment and limited resources in many developing countries. Drug repurposing was among the first ways to come up with a solution to combat the COVID-19 outbreak worldwide and save lives. Drug repurposing, well-defined as investigating new hints for approved drugs or progressing formerly considered but unapproved drugs, is the main approach in drug development. It is suggested that at least 30–40% of novel drugs and biologics permitted by the US Food and Drug Administration (FDA) in 2007 and 2009 can be considered repurposed or repositioned products. Here, we discuss some of the proposed and tested drugs as tools to eliminate COVID-19, the challenges and successes of preparing for future pandemics using the drug repurposing approach, and treating other diseases.

1. Introduction

In 2019, the whole world was hit by the outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that causes coronavirus diseases 2019 (COVID-19), with a huge economic and social burden to humankind [1]. Many people lost their household income. Many businesses were forced to shut down because of travel restrictions that were imposed to manage this novel disease. Sadly, millions of people lost their lives, and billions of cases were reported worldwide due to this disease. Unfortunately, there was no effective and affordable cure for COVID-19, resulting in the search for urgent treatment of this pandemic. Hence, pharmaceutical and academic institutions came together to develop emergency treatments. Thus, looking at existing drugs for the treatment of closely related diseases to COVID-19 was one of the proposed approaches to combat the scourge of the virus. Vaccines of tested efficacy to stop COVID-19 infection were being investigated vigorously worldwide. Currently, some specific drugs have been authorized for COVID-19, but the improvement of antivirals requires time. Hence, a faster way of treatment is done by drug repurposing [2, 3]. Drug repurposing is a promising approach in disease management because it is fast, easy, and a safe strategy to deal with ever-increasing disease crises because of their previously known applications. Drugs used for managing malaria were proposed for treatment of COVID-19. A study conducted showed that both chloroquine (CQ) and hydroxychloroquine (HCQ), which are known antimalarial medications, were found to have in vitro efficacy against SARS-CoV-2 [4]. Various small future studies have shown positive results. However, this outcome has not been declared worldwide, and apprehensions have been elevated due to the indiscriminate use and potential side effects. The clinicians were not in support of the usage of these medications. For example, the correct dose and duration of therapy are unknown. Another conducted study proposed that African countries have since seen low numbers of COVID-19 due to the endemic use of malarial drugs. They investigated the in vitro antiviral activity against SARS-CoV-2 of several antimalarial drugs. The outcome of the conducted study showed the following results: chloroquine (EC50 = 2.1 μM and EC90 = 3.8 μM), hydroxychloroquine (EC50 = 1.5 μM and EC90 = 3.0 μM), ferroquine (EC50 = 1.5 μM and EC90 = 2.4 μM), desethylamodiaquine (EC50 = 0.52 μM and EC90 = 1.9 μM), mefloquine (EC50 = 1.8 μM and EC90 = 8.1 μM), pyronaridine (EC50 = 0.72 μM and EC90 = 0.75 μM), and quinine (EC50 = 10.7 μM and EC90 = 38.8 μM) showed in vitro antiviral effective activity with IC50 and IC90 compatible with drug oral uptake at doses commonly administered in malaria treatment [5]. The ratio Clung/EC90 ranged from 5 to 59. Lumefantrine, piperaquine, and dihydroartemisinin had IC50 and IC90 too high to be compatible with expected plasma concentrations (ratio Cmax/EC90 < 0.05). With this data, it was then predictable that countries that generally use artesunate-amodiaquine or artesunate-mefloquine account for fewer cases and deaths than those using artemether-lumefantrine or dihydroartemisinin-piperaquine. In recent years, novel coronavirus infections have occurred occasionally in many countries worldwide. Severe acute respiratory syndrome coronavirus (SARS-CoV) arose in 2002, infecting 8,422 people and causing 916 losses during the epidemic. Middle East respiratory syndrome coronavirus (MERS-CoV) was first recognized in 2012. At the end of December 2019, a total of 2499 laboratory-confirmed cases of Middle East respiratory syndrome (MERS), including 861 associated deaths, were reported globally [6]. At the end of 2019, novel coronavirus pneumonia (NCP) appeared in Wuhan and spread speedily. The pathogen was established as a new coronavirus, publicly named COVID-19 by the World Health Organization (WHO). Proteinase is a key enzyme in CoV polyprotein processing. In recent years, research on SARS-CoV and MERS-CoV protease inhibitors has been carried out in vitro and in vivo. Lopinavir (LPV) is a proteinase inhibitor. Both peak (9.6 μg/ml) and trough (5.5 μg/ml) serum concentrations of LPV inhibit SARS-CoV [7]. LPV also blocks a postentry step in the MERS-CoV replication cycle [6]. Ritonavir (RTV) inhibits the CYP3A-mediated metabolism of LPV, thereby increasing the serum concentration of LPV. Lopinavir/Ritonavir (LPV/r) is a combination of lopinavir and ribavirin. The antiviral activity of LPV/r is like that of LPV alone, suggesting that LPV largely drives the effect. Therefore, this review focuses on drug repurposing their success and challenges, and preparedness for future pandemics [8].

2. Different types of human coronaviruses

Coronaviruses (CoVs) are a family of viruses that cause respiratory and intestinal illnesses in humans and animals. They usually cause mild colds in people, but the emergence of the severe acute respiratory syndrome (SARS) epidemic in China in 2002–2003 and the Middle East respiratory syndrome (MERS) on the Arabian Peninsula in 2012 show they can also cause severe disease. In addition to these types of coronaviruses, the whole world has been faced with the highly transmitted type of coronavirus since December 2019. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease, was first reported in China in 2019 in Wuhan after some serious pneumonia cases were reported [9]. This disease was first referred to as the 2019 coronavirus but later as COVID-19 by the World Health Organization (WHO). Below, each type of coronavirus is explained briefly and its structure.

2.1 SARS-CoV (the beta coronavirus that causes severe acute respiratory syndrome, or SARS)

Severe acute respiratory syndrome coronavirus was first identified in Southern China around November 2002, and in 2003, it was recognized as global human treatment due to its fast-spreading conditions. For example, this disease was reported in more than 24 countries such as Asia, Europe, Northern America, and Southern America. Despite the reported cases in those areas, in 2004, no cases were reported, and the risk was relatively low [10].

2.2 MERS-CoV (the beta coronavirus that causes Middle East Respiratory Syndrome, or MERS)

Middle East Respiratory Syndrome coronavirus (MERS-CoV) was first reported in Saudi Arabia in 2012 after that reported to some other parts of the countries such as Qatar and Jordan. However, as time passed, in 2018, MERS-CoV infection cases were reported worldwide such as Asia, Europe, America, and African countries. Therefore, more than 2260 confirmed cases and 803 deaths of MERS-CoV-related disease were reported worldwide, with most cases in Saudi Arabia. This disease attracted a lot of attention in pharmaceutical and academic industries due to its high rate of human-to-human transmission and treat to human. Also, to understand its origin and pathophysiology in order to prevent it from spreading father or becoming a human pandemic. Even though health officials were dealing with a relatively new virus with different behavior, they were able to be attended to and controlled quickly, thus reducing its threat to humans [11].

2.3 Human coronavirus (HCoV-NL63)

In Holland in 2004, another novel human coronavirus (HCoV-NL63) was isolated from a seven-month-old infant suffering from respiratory symptoms. This virus has subsequently been identified in various countries, indicating a worldwide distribution. HCoV-NL63 has been shown to infect mainly children and the immune-compromised, who presented with either mild upper respiratory symptoms (cough, fever, and rhinorrhea) or more serious lower respiratory tract involvement such as bronchiolitis and croup, which was observed mainly in younger children. In fact, HCoV-NL63 is the etiological agent for up to 10% of all respiratory diseases.

2.4 SARS-CoV-2 (the novel coronavirus that causes coronavirus disease 2019, or COVID-19)

In 2019 in China Wuhan city, the first reported cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) were announced as a virus responsible for coronavirus disease 2019 (COVID-19). This disease was then reported in various parts of the world, thereafter, declared as pandemic by World Health Organization (WHO) in 2020 [12, 13]. Millions of infections and millions of fatalities were reported worldwide due to fast spreading of this disease to human-human hosts. Most countries closed their borders to slow the spread of the virus, thus affecting many economies of developed and underdeveloped countries [14]. Current evidence suggests that the virus spreads mainly between people in close contact, for example, at a conversational distance. The virus can spread from an infected person’s mouth or nose in small liquid particles when they cough, sneeze, speak, sing, or breathe. Another person can then contract the virus when infectious particles that pass through the air are inhaled at short range (this is often called short-range aerosol or short-range airborne transmission) or if infectious particles come into direct contact with the eyes, nose, or mouth (droplet transmission) (WHO, 2021). Therefore, treatment to combat this disease was needed urgently. Hence, most developed countries invested many in pharmaceutical and academic institutions to foster the research and development of drugs or vaccines to treat millions of infected young and old people from different countries and ethnicities [15]. As a result, the FDA approved the use of various drugs known for treating other diseases, such as malaria. These drugs included famous malaria drugs such as chloroquine, hydroxychloroquine, and others, as shown in Table 1. The repurposed drugs target the entry points or strategies used by the virus to enter the human host system. For example, in Figure 1, the SARS-CoV-2 viral structure and proteins involved in the virus process are highlighted. Spike glycoprotein is a major role player during viral entry into the human host. Therefore, chloroquine is believed to block the virus's entry into the host and inhibit its replication inside the cellular system [22].

Table 1.

List of some drugs for malarial treatment but considered for COVID-19 treatment.

Figure 1.

SARS-CoV-2 virus depicting the location of the nucleocapsid (N), membrane (M), envelope (E), and spike (S) protein. (Adapted from Navhaya et al., 2023 unpublished data).

3. Impact of coronaviruses in the past and present

Since the outbreak of the first coronavirus in 2002 (SARS-CoV-1), then the outbreak of influenza A in 2009, which was followed by the MERS-CoV, in 2019, there was an outbreak of SARS-CoV-2 which was declared a global pandemic. SARS-CoV-2 produced the highest number of infections and fatalities compared to the other coronaviruses. It only did not affect the undeveloped countries, but well-developed countries were hit the most. It, therefore, caused a lot of panic in the health system worldwide. These viruses are somehow observed to produce the same symptoms individuals infected by them, from fever, cough, and shortness of breath to sore throats (Figure 2). Though there has been a huge drive to develop effective treatment or management of SARS-CoV, it is important to highlight some of the drugs proposed as tools to fight this pandemic [23].

Figure 2.

Summary of the impact of coronaviruses and influenza in the past and present.

4. Summary of malaria and its treatment

Malaria is one of the major causes of death, especially in underdeveloped countries. In Africa, many drugs have been approved to treat or manage malaria, such as chloroquine, hydroxychloroquine, ferroquine, and others, as listed in Table 1 were developed. However, the outbreak of COVID-19 in 2019 became a major concern as many countries worldwide were affected. The urgent treatment of the virus was needed; therefore, drugs that were meant for the treatment or management of the disease caused by Plasmodium parasites were proposed for the treatment of COVID-19. Below are some of the drugs that were tested or meant for the treatment of various types of Plasmodium species but repurposed or proposed for the treatment of SARS-CoV-2. Drug repurposing represents an enthusiastic mechanism to use approved drugs outside the scope of their original indication and accelerate the discovery of new therapeutic options [24].

5. Success, challenges, and preparedness for future treatment of COVID-19

Major success stories in the management of the COVID-19 were seen, and evidence is the scraping of travel regulations due to the decrease in the transmissions of the disease. The emergency approval of various vaccines, such as Pfizer, messenger RNA vaccine, protein subunit vaccine, MORDENA, and Johnson and Johnson vaccine, give hope to many people. However, challenges were reported regarding the intake of the vaccine in various parts of the world due to hesitations. This resulted in the slow intake of the vaccines and the boosters. As a result, various types of SARS-CoV-2 variants were developed in various countries, such as the United Kingdom, South Africa, and the United States just to mention but a few. One of the most important things to prepare for a future pandemic is the availability of accurate information. Proper education at all levels of age, in order to prepare better for what may come [25].

6. Cancer and HIV drugs repurposing for COVID-19 treatment

Both cancer and HIV are the pauses a huge threat to human life worldwide. With cancer, it is difficult to avoid because it can be inherently detected, but with HIV, it is documented that it can be transferred from human-to-human through unprotected sex and through sharing needles with someone who has the virus in their system. There is no effective cure for both diseases; however, there are management approaches. The outbreak of COVID-19 presented the opportunity for drug repurposing from both cancer and HIV drugs to treat the pandemic. Table 2 summarizes some drugs that are known for either cancer or HIV management but were tested for COVID-19 and were reported to be promising tools for this disease.

Drug name	Cancer/HIV	Action	Ref
Ruxolitinib	Cancer	Reduction of hyperinflammation during cytokine storm	[26]
Bevacizumab	Cancer	Vascular permeability inhibition	[27]
Carmofur	Cancer	Blockade of viral replication	[28]
Lopinavir	HIV	inhibits the activity of an enzyme critical for the HIV viral lifecycle	[28]
Ritonavir	HIV	binds to the protease active site and inhibits the activity of the enzyme	[29]
Indinavir	HIV	binds to the protease active site and inhibits the activity of the enzyme	[30]
Saquinavir	HIV	binds to the protease active site and inhibits the activity of the enzyme	[31]

Table 2.

A list of some drugs for cancer and HIV treatment but repurposed for COVID-19 treatment.

7. Conclusions and future perspectives

Drug repurposing is a promising tool in addressing various diseases, especially those that are still under study. The recent COVID-19 has taught us many lessons, from understanding its biology to drug development. Different types of drugs are being repurposed from the known disease to use against the treatment of coronavirus 2019. This approach has given many researchers and pharmaceutical industries to prepare for future pandemics using the same method to treat future pandemics.

Acknowledgments

This work was supported by South African Medical Research Council Self-Initiated Research (SIR) grants.