Drug repositioning is an alternative for the treatment of coronavirus COVID-19

Abstract

Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.

The recent spread of the novel coronavirus, SARS-CoV-2 has created a worldwide public health emergency. In December 2019, the outbreak of this emerging disease (COVID-19) began in Wuhan, China. It quickly spread, and a pandemic was declared by the World Health Organization in March 2020 [1,2].

Repositioning drugs already approved for use in humans is a useful tool to search for new therapeutic options, particularly in the current global crisis [3]. Thus, drug repositioning, also known as redirecting, repurposing, and reprofiling [4,5], emerges as an effective possibility for generating new treatments against COVID-19. Repositioning is defined as a new use of a drug, in addition to its original indication(s), and is an option for rapid identification of new therapeutic agents. The availability of drug-related information, such as pharmacokinetics, pharmacodynamics and toxicity [6], is an important advantage in the research efforts to quickly find an effective treatment for this deadly virus.

Table 1 presents a selection of recent studies that investigated the antiviral activity of several pharmacological classes, including antimalarial drugs and antibiotics, as options for repositioning as treatments of coronavirus (SARS-CoV, SARS-CoV-2 and HCoV-OC43) [7], [8], [9], [10]. A search was conducted on three databases (PubMed, SCOPUS and Web of Science) between March 15 th and March 27 th, 2020 using the following search strategy: [(repositioning) AND (repurposing) AND (redirecting) AND (reprofiling) AND (rediscovery) AND (COVID-19) AND (CORONAVIRUS) AND (treatment)] with review filters appropriate for individual databases. The inclusion criterion was studies that included the repositioning of drugs with antiviral activity against coronavirus. Duplicate cases were excluded, as were studies that did not address the issue.

Table 1.

Studies of the repositioning of drugs with effects against coronavirus.

Drug	Class	Original indication	New indication in repositioning	Type of study	Active concentration	Probable mechanism of action	Reference
Amodiaquine	4-amino-quinoline	Antiparasitic agent	SARS-CoV	In vitro	EC50 = 1.274	-	Dyall et al. 2014 [13]
Captopril	ACE-2 inhibitor	Hypertension	SARS-COV-2	Hypo-thesis	-	Inhibits binding between COVID-19 and human ACE-2, and reduces symptoms of severe pneumonia	Sun et al. 2020 [14]
Chloroquine	4-amino-quinoline	Antimalarial	SARS-CoV	In vitro	EC50 = 6.538	-	Dyall et al., 2014 [13]
			SARS-CoV	In vitro	IC50 = 8.8 µM	-	Keyaerts et al., 2004 [15]
			SARS-CoV	In vitro	EC50 = 4.1 µM CC50 ≥ 128 µM	-	de Wilde et al., 2014 [16]
			SARS-CoV-2	In vitro	EC50 = 1.13 µM	Probably blocks virus infection by increasing endosomal pH required for virus/cell fusion, and interferes with glycosylation of cellular receptors of SARS-CoV	Wang et al., 2020 [7]
			SARS-CoV-2	In vitro	EC50 = 2.71 µM	Blocks virus transport between cell organelles	Liu et al., 2020 [9]
			SARS-CoV-2	In vitro	EC50 = 5.47 µM		Yao et al., 2020 [17]
			SARS-CoV-2	Comput-ational	-	-	Gordon et al., 2020 [18]
			SARS-CoV-2	In vivo	-	-	Gao et al,, 2020 [8]
			HCoV-OC43	In vivo	EC50 = 0.3 µM	Probably affects endosome-mediated fusion	Keyaerts et al., 2009 [19]
Cyclosporin A	Calcineurin inhibitors	Immuno-supressant	SARS-CoV	In vitro	16 µM	Likely that the drug interferes with functional interactions between viral proteins and one or multiple members of the large cyclophilin family	de Wilde et al., 2011 [20]
			SARS-CoV	In vitro	EC50 = 3.3 µM	Affects replicative protein	Pfefferle et al., 2011 [21]
Chlorpromazine hydrochloride	Antipsychotic	Schizophrenia	SARS-CoV	In vitro	EC50 = 8.8 µM CC50 = 24.3 µM	-	de Wilde et al., 2014 [16]
Clomipramine	Neurotransmitter inhibitor	Antidepressant	SARS-CoV	In vitro	EC50 = 13.2 µM	-	Dyall et al., 2014 [13]
Disulfiram	Tiuram dissulphide	Chronic alcohol dependence	SARS-CoV	In vitro	IC50 = 24.1 µM	Competitive inhibitor of SARS-CoV papain-like protease	Lin et al, 2018 [22]
Enalapril	ACE-2 inhibitor	Hypertension	SARS-COV-2	Hypo-thesis	-	Inhibits binding between COVID-19 and human ACE-2, and reduces symptoms of severe pneumonia	Sun et al., 2020 [14]
Gemcitabine hydrochloride	DNA metabolism inhibitor	Anticancer	SARS-CoV	In vitro	EC50 = 4.9 µM	-	Dyall et al., 2014 [13]
Hydroxychloroquine	4-amino-quinoline	Antimalarial	SARS-CoV	In vitro	EC50 = 7.9 µM	-	Dyall et al., 2014 [13]
			SARS-CoV-2	In vivo	0.46 µg/mL (serum concentration)	-	Gautret et al., 2020 [11]
			SARS-CoV-2	In vitro	EC50 = 2.71 µM	Blocks virus transport between cell organelles	Liu et al., 2020 [9]
			SARS-CoV-2	In vitro	EC50 = 0.72 µM	-	Yao et al., 2020 [17]
Dasatinib	Kinase signaling inhibitor	Anticancer	SARS-CoV	In vitro	EC50 = 2.1 µM	-	Dyall et al., 2014 [13]
Imatinib mesylate	Kinase signaling inhibitor	Anticancer	SARS-CoV	In vitro	EC50 = 9.8 µM	-	Dyall et al., 2014 [13]
Loperamide	Opioid	Antidiarrheal	SARS-CoV	In vitro	EC50 = 5.9 µM CC50 = 53.8 µM	-	de Wilde et al., 2014 [16]
Mefloquine	Aminoquinoline	Antiparasitic agent	SARS-CoV	In vitro	EC50 = 15,5 µM	-	Dyall et al., 2014 [13]
Metformin	Biguanide	Diabetes	SARS-CoV-2	Comput-ational	-	-	Gordon et al., 2020 [18]
Nitazoxanide	Nitrothiazole	Antimalarial	SARS-CoV-2	In vitro	EC50 = 2.12 µM	-	Wang et al., 2020 [7]
Promethazine hydrochloride	Neurotransmitter inhibitor	Antihistamine	SARS-CoV	In vitro	EC50 = 7.5 µM	-	de Wilde et al., 2014 [16]
Remdesivir	Nucleoside analog	Clinical development for treatment of Ebola virus infection	SARS-CoV-2	In vitro	EC50 = 0,77 µM; IC 50  > 100 µM	Adenosine analogue incorporates into nascent viral RNA chains and results in premature termination	Wang et al., 2020 [7]
Tamoxifen	Estrogen receptor inhibitor	Breast cancer	SARS-CoV	In vitro	EC50 = 92.8 µM	-	Dyall et al., 2014 [13]
Terconazole	Sterol metabolism inhibitor	Antifungal	SARS-CoV	In vitro	EC50 = 92.8 µM	-	Dyall et al., 2014 [13]
Toremifene	Estrogen receptor inhibitor	Breast cancer	SARS-CoV	In vitro	EC50 = 11.9 µM	-	Dyall et al., 2014 [13]
Teicoplanin	Glycopeptide antibiotic	Bacterial infection	SARS-CoV-2	In vitro	IC50 = 1.66 µM	Inhibited entry of 2019-nCoV pseudovirus, which provides a possible strategy for prophylaxis and treatment for 2019-nCoV infection	Zhang et al., 2019 [10]

(-) Not determined

The analysis revealed seven studies that address drug repositioning against SARS-CoV-2; the target drugs were chloroquine, hydroxychloroquine associated with azithromycin, teicoplanin, remdesivir, nitazoxanide and metformin. Several authors report the potential of chloroquine as a therapeutic option against this virus: in vitro it presented an EC₅₀ of 1.13 µm and in vivo it caused a negative conversion of the virus in more than 100 patients who were participating in multicenter clinical trials conducted in China [7,8]. In the in vitro study performed by Liu et al. (2020), both chloroquine and hydroxychloroquine inhibited the virus from entering the cell and, at later cell stages of SARS-CoV-2 infection, blocked virus transport between cell organelles, which is considered a determining step for the release of viral genome in cells in the case of SARS-CoV-2. However, chloroquine was observed to have a higher efficacy [9].

Teicoplanin, on the other hand, presented an in vitro IC₅₀ of 1.66 µM, a relatively low active concentration, which is promising for its use against SARS-CoV-2; however, this requires further in vivo verification and incorporation in clinical trials [10].

Gautret et al. (2020) conducted a clinical trial using hydroxychloroquine in patients infected with SARS-CoV-2. The initial results show a significant reduction in viral carriage and the use of hydroxychloroquine in conjunction with azithromycin was more efficient in eliminating the virus [11]. There is also expectation for the results of the WHO solidarity initiative, which consisted of a worldwide call for a clinical study to simultaneously research the efficacy of four drugs, including remdesivir, chloroquine and hydroxychloroquine, for the treatment of patients affected with COVID-19 [12]. Thus, drug repositioning is a promising alternative for the treatment of COVID-19 disease, and a more complex investigation of the antiviral effect of these molecules against SARS-CoV-2 is encouraged.