|Ahead of print publication
Repurposing drugs: Lessons from rheumatology in the COVID-19 pandemic
Manesh Manoj, Prashant Bafna, Rasmi Ranjan Sahoo, Kasturi Hazarika, Anupam Wakhlu
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow, Uttar Pradesh, India
|Date of Submission||29-Nov-2020|
|Date of Acceptance||07-Feb-2021|
Department of Clinical Immunology and Rheumatology, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Humanity currently faces one of its biggest challenges, created by a tiny quasi-life form, the severe acute respiratory syndrome coronavirus 2. The rapidity of spread and the enormous burden placed on public health infrastructure by the coronavirus disease 2019 (COVID-19) pandemic has forced researchers to look for quick answers for therapy. Drug repurposing is probably the quickest way to develop an effective therapy in a very short time. With additional input from artificial intelligence (AI), drug repurposing may emerge as one of the major techniques by which humanity can overcome this as well as future challenges. The field of rheumatology has been one of the biggest benefactors of drug repurposing. This article reviews the various ways drugs used in rheumatological disorders are being repurposed for possible COVID-19 treatment. An overview of other nonantiviral drugs being repurposed is also undertaken, and the role of AI in drug repurposing is touched upon.
Keywords: Artificial intelligence, bacillus Calmette–Guerin, cytokine storm, drug repositioning, drug repurposing, vaccinology
| Introduction|| |
The world is in the grip of one of the biggest health-care crisis in recent history. What began as a case report of an atypical pneumonia in Wuhan, China, in December 2019 has evolved into one of the largest pandemics ever. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is highly effective in infecting scores of people in a relatively short period of time, and a small but significant percentage of patients with coronavirus disease (COVID-19) progress to severe, life-threatening disease, mainly involving the lung, with a significant number having a “cytokine storm” during later stages of the infection. At the time of preparation of this article, about 60 million people worldwide have been infected and almost 1.5 million people have succumbed to this scourge. Moreover, these numbers appear far from plateauing with the occurrence of a second or even a third peak in several countries. The elderly, pregnant women, and those with comorbidities, especially diabetes and hypertension, tend to have a worse prognosis.
The rapidity of spread of the disease and the heavy burden it has posed on health-care systems is forcing researchers for rapid drug and vaccine development against the virus. A number of clinical trials are underway with a variety of drugs and the medical community is eagerly looking forward to their results though so far it has been disappointing. This review aims to describe the various drugs used in rheumatology which have been repurposed for possible therapy in COVID-19, as well as an overview of other repurposed drugs and vaccine strategies that are being evaluated for the disease, and the role artificial intelligence (AI) has played in the fight against the SARS-CoV-2 virus.
| Search Strategy|| |
PubMed engine was used to search for articles using the MeSH terms “drug repurposing,” “drug repositioning,” “drug repurposing AND covid,” “drug repositioning AND covid,” “artificial intelligence AND drug repurposing,” “cytokine storm AND covid,” and “deep learning.” Review articles in the English language within the past 5 years (October 2015 to October 2020) and those with relevance to humans, where possible, were selected. Out of a total of about 3861 articles, about 193 articles were selected for review on the basis of relevance to the topic and with the consensus of the authors. The website www.ClinicalTrials.gov was used to search for trials of each drug which are recruiting, active, and not recruiting or completed. The references in each article were further reviewed as necessary. A flowchart representing the article selection process is detailed in [Figure 1].
| Drug “Repurposing” or “Repositioning”|| |
The identification of drugs previously developed or under development for use in other indications or even those whose development has been abandoned, that can act on other targets for an entirely different indication, is called drug “repositioning” or “repurposing.” Repurposing of drugs has a number of advantages. It enables more rapid drug development, and the drugs that are repurposed would have already gone through Phase I trials., This saves time and money, with present estimates of time and cost for developing a new drug taking 13–15 years on average and reaching 3 billion US$, respectively. In contrast, it is predicted that a repurposed drug will cost around 40–80 million US$ and take 3–12 years for development and marketing. Historical examples of drugs being used more for their repurposed indications than their primary indications include sildenafil citrate which was initially developed as an antihypertensive agent and thalidomide which was marketed in the 1950s as a sedative and antiemetic agent. [Table 1] summarizes the various approaches for repurposing of drugs.
| Drugs Used in Rheumatology Repurposed for COVID-19|| |
They are probably the most talked of class of drugs used in the therapeutic armamentarium against COVID-19, with a fair bit of world politics and mainstream media exposure. Hydroxychloroquine (HCQ) has been repurposed several times in its history from being developed as an antimalarial, to being one of the most prescribed drugs in rheumatology to treating several indolent infections such as Q fever and Whipple's disease, and now being used against the SARS-CoV-2 virus. These drugs inhibit virus entry in vitro by interfering with membrane fusion and internalization along with increasing the pH of the endosome. There is impairment of terminal glycosylation of the angiotensin-converting enzyme 2 (ACE2) receptor required for virus fusion with the host cell in studies with chloroquine, and in silico analysis has revealed that these drugs may also possibly prevent the binding of viral spike proteins to gangliosides on the cell surface, required for interaction with the ACE2 receptor. It has been suggested that by reducing CD154 (or CD40 L) expression on the surface of T-cells, these drugs may attenuate the cytokine storm response in the later phases of COVID-19 infection., Most human studies in COVID-19 have used HCQ due to its better side effect profile. Conflicting reports of the drug's efficacy have emerged, though trial design issues were present., This class of drugs has also received a lot of negative publicity (with regard to exaggerated claims of severe side effects). A sudden surge in demand for the drug led to a shortage of the drug in pharmacies. Undue concern about retinopathy has also been a problem, mainly among nonrheumatologists. The editorial by Marmor MF in the American Journal of Ophthalmology should put these fears to rest. Pre-screening of selected groups of patients including elderly, those with preexisting heart disease and those taking drugs which prolong QT interval would prevent cardiotoxicity of HCQ. Its efficacy in vivo has been questioned and a consensus is yet to be reached on its role in prophylaxis or therapy and the optimum dose to be used.,
It has been suggested that following the virus entry into the cell, there is activation of endosomal TLR7 and production of high levels of interferon-alpha (IFN-α), tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-12. Uncontrolled production of these inflammatory molecules, associated with a defective adaptive immunity, may precipitate the dreaded cytokine storm phase of COVID-19. This is akin to the cytokine storm seen in patients treated with chimeric antigen receptor-T (CAR-T) cells in which tocilizumab has been used successfully in the past. Estimation of serum IL-6 levels and elevated D-dimer levels >1000 ng/ml may guide selection of patients. The American College of Rheumatology (ACR) COVID-19 clinical guidance for adult patients with rheumatic diseases suggests that in certain circumstances, as part of a shared decision-making process, IL-6 inhibitors may be continued in patients who are suspected or are confirmed to have the disease. Another IL-6 inhibitor developed for RA and being repurposed for COVID-19 is sarilumab (IL-6 receptor antagonist), but the results so far have been disappointing. Other agents of this class being considered include clazakizumab and siltuximab. A trial of these agents in combination with IL-1 inhibitors is also underway (COV-AID trial).
Many patients in the cytokine storm phase of COVID-19 also have features suggestive of secondary hemophagocytic lymphohistiocytosis, with hyperferritinemia and other laboratory abnormalities suggesting a severe hyperinflammatory state. IL-1 inhibition is predicted to be beneficial in this group of patients, and anakinra (IL-1 receptor antagonist) had shown some benefits in uncontrolled trials in such severely ill patients., However, the ANACONDA-COVID-19 trial had to be suspended early due to excessive mortality in recipients. Canakinumab (IL-1β antagonist) is also undergoing trials in patients with COVID-19 pneumonia.
Janus kinase inhibitors
Baricitinib, a JAK1/2 inhibitor, has been suggested as a possible agent against SARS-CoV-2 virus. With additional AAK1 inhibitory properties and with the help of bioinformatics (described later), it was predicted that baricitinib may interfere with viral entry in to the host cell. Further, Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway inhibition may attenuate the later phase of immunological injury in the disease. A counterargument against the drug is the possibility of facilitation of viral replication due to impaired IFN secretion. Previously reported adverse effects, with respect to increased viral infections, may not occur with the short duration of use in this condition. Tofacitinib is also being investigated in symptomatic interstitial pneumonitis due to COVID-19 though the lack of action on JAK2 (IL-6 production depends mainly on JAK2 signaling) and AAK1 may hinder its success. Another JAK inhibitor ruxolitinib is in trials for COVID-19. The recent ACR guidance statement has recommended stopping this class of drugs when a person is diagnosed with or suspected to have COVID-19. A trial of a nebulized lung-selective, pan-JAK inhibitor (TD-0903; Theravance Biopharma) in COVID-19 patients is also underway.
It is an antimitotic drug, which is the cornerstone of treatment in gout and has been used in several other inflammatory conditions, including familial Mediterranean fever More Details. It causes microtubular remodeling, thereby preventing NOD-like receptor pyrin domain-3 (NLRP3) inflammasome activation and clathrin-mediated endocytosis., In animal studies of ARDS, NLRP3 activation was found to be a component in development of acute lung injury. SARS coronavirus (SARS-CoV) viral proteins, viroporin S, 3A, and 8A required for viral replication, were found to activate this inflammasome further complicating the pathogenesis of ARDS., For COVID-19, colchicine may play a role at multiple levels. First, it would prevent endocytosis of the virus into the host cell. Second, by inhibiting NLRP3 activation, it decreases the cytokine storm (IL-1β, IL-6, and IL-18)-related lung injury, and third, it is thought to decrease myocarditis seen in patients with COVID-19 patients.
Anti-tumor necrosis factor-alpha inhibitors
The SARS-CoV was found to cause ACE2 receptor shedding with increased TNF-α-converting enzyme activity associated with increased TNF-α production, which then played a significant role in further lung injury. Due to similarity in receptor binding with the SARS-CoV-2 virus and the prominent role played by TNF-α in severe disease, these agents have been suggested to have a role in preventing severe lung inflammation in COVID-19 pneumonia. Data from the SECURE-IBD registry suggest that COVID-19 patients, on anti-TNF agents for inflammatory bowel disease, do just as well and possibly better than those on alternative agent. A Chinese study with adalimumab is underway (ChiCTR2000030089).
Sildenafil, a phosphodiesterase (PDE)-5 inhibitor, has been used extensively in rheumatology to treat Raynaud's phenomenon and is considered to have anti-inflammatory and antifibrotic properties. The ability to modulate pulmonary vascular resistance, with increased nitric oxide levels in the pulmonary vessels, and its antifibrotic properties have led researchers to suggest its use in COVID-19 pneumonia. Apremilast, a PDE-4 inhibitor which increases intracellular cyclic AMP levels, may indirectly modulate the production of inflammatory mediators attenuating the hyperinflammatory phase of COVID-19 and is being currently investigated (I-SPY COVID-19 trial).
Cyclosporine A has been shown to have antiviral properties against multiple coronaviruses in vitro. FK506 (tacrolimus) is a relatively better tolerated calcineurin inhibitor, and FK506-binding proteins have been shown to be interaction partners with the nonstructural protein 1 of SARS-CoV virus. It shows good in vitro activity against SARS-CoV and various other coronaviruses. This group of drugs may also attenuate the cytokine storm phase of COVID-19. The ongoing TACROVID study aims to evaluate the effect of tacrolimus and steroid pulses in COVID-19 patients with severe disease.
[Table 2] contains the details of the doses of drugs used in various trials. Thalidomide, a glutamic acid derivative, a potent inhibitor of TNF-α, IL-1β, IL-6, and IL-12, has shown a protective action on lungs in H1N1-infected mice, leading to plans for trials in COVID-19. Mycophenolate mofetil (MMF) had shown promise in vitro against the Middle East respiratory syndrome-related coronavirus, but in vivo studies showed negative effects. At present, there are no studies regarding the use of MMF in COVID-19 patients. Leflunomide has also shown significant antiviral effects against cytomegalovirus infection but is presently not in consideration in COVID-19 patients.
|Table 2: Doses of rheumatological drugs used in various clinical trials for coronavirus disease-19|
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| Other non-antiviral Drugs Being Repurposed for COVID-19|| |
It is a Food and Drug Administration-approved antiparasitic drug, which was found to have wide-spectrum antiviral activity in vitro including against SARS-CoV-2. It acts by preventing entry of viral cargo protein from the cytoplasm to the nucleus by destabilizing IMPα/β (importin), which is essential for viral transport resulting in reduction of viral replication. An in vitro study by Caly et al. showed that a single dose of ivermectin decreases viral RNA levels by 5000-fold within 48 h, accounting for a 99.98% reduction in the viral load. Addition of ivermectin to HCQ was hypothesized to cause a synergistic action against the virus, where HCQ prevents the entry of virus while ivermectin inhibits the replication of virus, if entry occurs. These results are promising but need to be proven in clinical studies.
Ascorbic acid (Vitamin C)
The proposed mechanisms of Vitamin C immunomodulatory effects are increased production of type I IFNs, enhanced natural killer cell activity, and modulation of neutrophil function, forming the basis for its use in common cold and overwhelming infections in the past. Clinical trials have shown mortality benefit with high-dose Vitamin C (200 mg/kg) in patients with ARDS at 1 month, but more research is needed to validate this outcome. Multiple trials are ongoing to assess the therapeutic role of adjunctive Vitamin C in COVID-19 patients.
In the current COVID-19 pandemic, Vitamin D has received great attention for its immunomodulatory properties. It helps to maintain cellular tight and gap junctions and the adherence of the epithelial cells, thus acting as physical barrier against the virus. Vitamin D is required for release of antimicrobial agents such as cathelicidins and defensins. These agents have broad-spectrum antiviral activity, in which defensins have been found to have additional anti-SARS-CoV activity. It may also reduce proinflammatory cytokines such as TNF-α and IFN-γ by suppressing T-helper cell type 1 response and promotes induction of FOX-P3 regulatory T-cells contributing to the anti-inflammatory response, there-by limiting the cytokine storm in patients with COVID-19. As compared to calcium regulating effects, higher levels of 25-hydroxyvitamin D (25(OH)D) are postulated to be required for its immunomodulatory effect. A study suggested maintaining 25(OH)D levels at least above 50 ng/ml in these patients. Doses ranging from 50,000 IU up to 400,000 IU have been used in trials.
The World Health Organization suggests that up to a third of the world's population has zinc deficiency. Zinc is essential for maintenance of normal ciliary function in the respiratory epithelium in turn facilitating viral clearance. It is also essential in the normal function of epithelial tight junction proteins such as claudin-I and ZO-I. Zinc may also negatively modulate ACE2 expression reducing viral entry. A direct inhibitory effect on viral replication has also been shown in experimental studies. The anti-inflammatory, antioxidant, and immunomodulatory effects of zinc have led to its use as an adjunctive therapy in COVID-19 patients, and a number of trials are underway.
Several other nonantiviral drugs which are under consideration for treating COVID-19 and their basis for use are listed in [Table 3]. [Figure 2] shows the proposed sites of action of various drugs being tried in COVID-19.
|Figure 2: Schematic diagram showing the proposed sites of action of various drugs being tried in COVID-19. ARB: Angiotensin receptor blocker; AT1R: Angiotensin 1 receptor; ACE: Angiotensin-converting enzyme; TMPRSS2: Serine protease enzyme; AAK1: AP2-associated protein kinase 1 TLR: Toll-like receptor; PDE: Phosphodiesterase; JAK: Janus kinase; STAT: Signal transducer and activator of transcription proteins; NO: Nitric oxide; NET: Neutrophil extracellular traps; IL: Interleukin; INH: Inhibitor; TNF: Tumor necrosis factor; Adapted with permission from the author, Source – Misra DP, Agarwal V, Gasparyan AY, Zimba O. Rheumatologists' perspective on coronavirus disease 19 (COVID-19) and potential therapeutic targets. Clin Rheumatol 2020;39:2055-62|
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|Table 3: Other non-antiviral drugs considered for repurposing and their basis for use in coronavirus disease-19|
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| Repurposing with Vaccines: The Bacillus Calmette–Guerin Story|| |
The bacillus Calmette–Guerin (BCG) vaccine enhances nonspecific protection against nonmycobacterial pathogens causing respiratory tract infection by induction of innate immune memory referred to as “trained immunity” in contrast to the specific “memory” of the adaptive immune system. BCG causes reprograming of monocytes by epigenetic and histone modification at the promoter site of genes encoding for inflammatory cytokines (IL-1β and TNF) responsible for IFN release, resulting in enhanced inflammatory response to viral pathogens such as influenza and yellow fever. This antiviral response of BCG vaccine is the basis for its research in health-care workers in Australia (BRACE trial) and The Netherlands (BCG-CORONA trial). The WHO currently does not recommend using BCG vaccine against COVID-19, as there is no evidence yet to suggest its antiviral activity against SARS-CoV-2.
| Role of Artificial Intelligence in Drug Repurposing|| |
In today's clinical practice, the availability of latest, peer-reviewed information regarding every aspect of patient care, as well as associated topics, allows quicker, more accurate diagnosis and also plays an important role in the continuous education of a physician. Patient care in the outpatient departments and their follow-up have been revolutionized with the advent of AI. Even though a majority of patients in developing countries are yet to reap the benefits, AI appears to be capable of revolutionizing the future of medical care as a whole. One component of AI is the use of machine learning (ML), where machines use statistical methods to analyze data and help in improving the response with experience. A further subset of ML is the process of deep learning (DL), where machines train themselves to perform tasks.,,
The use of AI in characterization of the virus, epidemiology of the infection, and in the possible development of therapeutics in a very short span of time has been indispensable for humanity's fight against this pandemic. Recently, AI-facilitated drug repurposing has been in the limelight due to the SARS-CoV-2 pandemic. These “in silico” methods take advantage of DL techniques incorporating data about the various characteristics of each drug in a large database on one side and the characteristics of the target protein or organism on the other – a sort of mix and match at the molecular level.
Ge et al., using AI (data-driven drug repositioning framework), suggested that a poly-ADP-ribose polymerase 1 inhibitor, CVL218, which is presently being developed to treat gliomas, showed significant antiviral activity without toxicity in animal models and could be considered in COVID-19 pneumonia. Another excellent example is the suggestion by Richardson P et al. about the possible use of baricitinib in hospitalized patients with COVID-19. Using AI, they initially identified a potential target protein on the SARS-CoV-2 virus (AP2-associated protein kinase 1 or AAK1 involved in endocytosis of the virus particle) and then used DL to compare therapeutic potential of drugs already being used in humans. They identified baricitinib as a high-affinity AAK1 inhibitor with a required dose for inhibition similar to that used in rheumatoid arthritis patients. The group also evaluated the possible use of other JAK inhibitors such as fedratinib, ruxolitinib, sunitinib, and erlotinib, but they were found to have AAK1 inhibitory properties only at much higher doses than used in clinical practice. These examples reveal the possible potential of AI in developing therapeutics for new as well as difficult clinical conditions.
Not only drug repurposing but also the development of new drugs against SARS-CoV-2 may be facilitated by AI-dependent techniques. With the concept of “chemical space” with up to 1060 possible molecules, there may be a large number of as-yet undiscovered molecules with high affinity for the various viral proteins which can be targeted. It is humanly impossible to select these molecules in a short span of time. AI can enable rapid selection of these potentially clinically useful molecules, thus speeding up the drug discovery process.
Another important field where AI has had a significant impact is in vaccine development. The process of reverse vaccinology uses AI to identify target proteins in bacteria or virus which can mount an antigenic response, and these are then incorporated into vaccines. The first such vaccine produced was against meningococcus B almost 20 years back by Rappuoli et al. Even though there has been very slow progress in this field so far, it is still a good example of the potential of AI in health care. Recently, reverse vaccinology is being utilized in developing vaccines against SARS-CoV-2 as well.
| Relevance of Drug Repurposing in Rheumatology|| |
The history of therapeutics in rheumatology is littered with examples of drugs being repurposed ranging from gold salts and methotrexate to biologic agents. Drug repurposing in rheumatology can be divided into two phases – an initial phase of serendipitous drug discovery and a modern phase of disease-targeted drug discovery. Only a few drugs such as glucocorticoids, leflunomide, and the newer biologic agents can claim to have been developed for rheumatological indications. Drugs such as anti-TNF-α agents and IL-1 inhibitors were initially developed as therapeutic agents in sepsis, and a number of oncological drugs have been repurposed to treat rheumatic diseases over the years. Greater knowledge of disease pathogenesis, advances in omics studies, and the increasing influence of AI, especially DL, has opened up new avenues. The reader is encouraged to refer to some excellent reviews about the colorful history of drug repurposing in rheumatology.,
| Conclusion|| |
The challenges posed by the ongoing pandemic have put a lot of questions about the preparedness of humanity to deal with such a medical catastrophe and have reinforced governments to recognize the importance of medical research and health-care infrastructure for the future of humanity. The need for quick, safe, and effective drugs to treat the disease has led to a resurgence of AI-assisted drug repurposing techniques. Various factors such as stringent drug safety and clinical trial requirements make developing an entirely new drug a daunting task today. This pandemic has shown that with the help of highly advanced AI and the close collaboration of a number of fields such as clinicians, geneticists, biochemists, pharmacists, and computer experts, drug repurposing as well as new drug and vaccine development will continue to set new landmarks at a pace like never before.
The authors would like to express their gratitude to Dr. Durga Prasanna Mishra, Assistant Professor, Department of Clinical Immunology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, U.P., for his guidance and critical inputs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3]