Repurposing antiviral drugs on recently emerged viral infections: A review article.

Finer understandings of drugs, for newly emerged diseases are becoming difficult nowadays. The contemporary approach is Drug Repurposing. Drug repurposing implies the exploration of surviving drugs for new restorative motive. Apart from conventional drug approaches, it is a profitable, brisk and reliable approach. The equivalent therapies for newly emerging and remerging viral infections are strenuous spot these days. The drug repurposing has helped in treating many viral reprofiling infectious diseases like CoVID-19, MERS, SARS, Influenza, Swine flu, Hanta, Zika, Ebola, Marburg, Human Adeno virus infection etc. The present review looks at describing the drug repurposing approach in various viral infections.

Introduction

The world has abundant and diverse forms of viruses Table 5. The viruses like particle per biome in association with humans are 2.80 × 1022. With the outbreak of emerging and remerging viral infections research has been put forth to develop new drugs on new targets and mechanism. Center for Drug Evaluation and Research (CDER) of FDA’s approved 48 novel drugs during period 2019. From past 10 years, 2010–2018, CDER has averaged about 37 novel drugs (www.fda.gov). Nevertheless, the WHO and governments faces global ultimatum of emerging and remerging viral infections. Some infections viral diseases, which lack determined treatment, are CoVID-19, MERS, SARS, Influenza, Swine flu, Hanta, Zika, Ebola, Marburg, Human Adeno virus infection.

Table 5

Infection and place of origin.

Infection	Year of isolation	Place of origin
CoVID-19	2019	Wuhan city in China
MERS-CoV	2012	Saudi Arabia
SARS-CoV	2002	Guangdong state in China
Influenza	1918	United States
Swine Flu	2009	Mexico
Hanta virus infection	1950 s	United States
Zika Virus Infection	1947 1952 (human case)	Uganda
Ebola Virus Infection	1976 2013 (recent)	Democratic Republic of Congo (Zaire) Guinea
Marburg viral Infection	1967	Marburg, Frankfurt
Human Adeno Viral Infection	1955	Great Britain

Drug repurposing

Drug repurposing is also known as Redirecting, Repurposing, Repositioning, Reprofiling, Retasking, Rescuing and Therapeutic switching. It means development of new therapeutic purpose from old drugs. On average, hit ratio in development of new drug molecule is 2.01%.

Traditional approach take long time to develop a new drug molecule when compared to repurposing drug approach as explained in Fig. 1, Fig. 2. Therapeutic switching is the foremost, riskless and economical approach in treatment of recently emerging and remerging infections Table 5. Nowadays repurposing of drugs is secured and reliable strategy in pharmaceutical sectors.

Fig. 1

Traditional Drug Discovery Approach with time Period.

Fig. 2

Repurposing of the drug approach with time period.

Methods

Repurposing drugs of CoVID-19 infection

Covid19 Infection is severe acute novel respiratory disease called corona virus 2019. It is caused due to corona virus of family Coronaviridae Candidate antiviral repurposing drugs for CoVID-19 infection:

Investigational drugs

Remedesvir and favipiravir are investigational drugs Table 1.

Table 1

Types of drugs.

Drugs	Used in therapy	Mechanism of action	References
Lopinavir	Treatment of HIV infections	---------	[1]
Ritonavir	Treatment of HIV infections	--------	[1]
Ribavirin	Treating in hepatitis C, RSV infection, viral hemorrhagic fevers	--------	[1]
Oseltamivir	Antiinfluenza	Neuroaminidase inhibitor	[1]
Umifenovir (Arbidol)	Antiinfluenza	Target S protein or interact with ACE2, inhibit membrane function	[1]
Miscellaneous agents	Like Interferon alpha and beta	-------	[1]

Pangolin corona virus: GXP2V

Three antiviral drugs are: CEP, selamectin and mefloquine hydrochloride

Protease (Mpro)/ 3CLpro inhibitors

Cinanserin- serine antagonist – active against SARS COV-1

Herbacetin

Rhoifolin antioxidant activity with association of disease such as Alzheimer’s,

Flavonoids Atherosclerosis show effective inhibition of SARS COV-1pro

pectolinariam

Papain-like (PLpro) inhibitor – Disulfiram-

Inhibitors of spike proteins – Griffithsin

Repurposing drugs of middle east respiratory syndrome coronavirus (MERS-CoV)

Convalescent plasma and immunoglobulin, Interferons, Protease inhibitors.

Repurposing drugs of severe acute respiratory syndrome corona virusTable-2SARS-CoV)

.

Drugs

Anti-Biotic Therapy

Anti-viral Therapy

Ex: Ribavarin, Neurominidase Inhibitor(Oseltamivir phosphate)

Repurposing drugs of Influenza virus infection Table 3

Influenza is a contagious respiratory viral infection caused due to influenza A (20 subtypes: H1-H20) and influenza B in humans which belongs to the family orthomyxoviridae. It has segmented negative RNA. It is pleomorphic and enveloped with helical capsid. Viral genome is composed of single negative stranded RNA and with eight nucleoprotein segments. Virus is composed of surface glycoproteins which includes neuraminidase (NA) and hemagglutin (HA), nucleoprotein (N), matrix protein (M) and non-structural proteins (NS1 and NS2) Table 7. [1] First case observed in 1918 in united states, Europe and Asia. Influenza virus binds to sialic acid through HA receptor with α(2–3) linkage. [2], [3], [4], [5] The clinical features include fever, body ache, cough and runny nose. Influenza virus transmitted specifically through ciliated pseudo stratified columnar respiratory epithelial cells of respiratory tract [6].

Table 7

Directly acting antiviral drugs.

Drugs	Mode of action
7-deaza-2-CMA	RdRp inhibitor
NITD008	Pyrimidine synthesis inhibitor
BCX4430 *	RdRp inhibitor
Sinefungin	Pan-methyltransferase inhibitor
Myricetin, quercetin, luteolin, isorhamnetin, apigenin, curcumin	NS2B-NS3 protease inhibitor
Niclosamide, and nitazoxanide	NS2B-NS3 protease inhibitor

Repurposing drugs of Swine flu Table 4

Swine flu infection is a respiratory disease caused by Influenza A (H1N1) belonging to the family Orthomyxovirus.

Repurposing drugs of Hanta virus

Hantavirus infection is caused due to single stranded negative chain RNA virus belonging to the family Hantaviridae of order Bunyavirales which are transmitted by rodent animals (mice, mouse, rat etc.) through faeces, saliva (droplets and aerosols) and urine and infrequently through bites of infected animals.

The major challenge nowadays is intervention treatment for hanta virus particularly HPS cases.

ETAR, Favipiravir, Ribavirin (RBV), Lactoferrin, Vandetanib, Corticosteroids, Immunotherapy Monoclonal Antibodies (These are evaluated by passive transfer), Immunotherapy-Polyclonal Antibodies:

Hantavirus DNA vaccine is currently in progress.

Repurposing drugs for Zika virus infection Table 6

Repurposing drugs for Ebola virus infection

Ebola disease is known as Ebola haemorrhagic viral disease. It is caused due to the Ebola virus which belongs to the family filoviridae and order mononegavirales.

Drugs: Chloroquine, Amodiaquine, Clomiphene and Toremiphine, Interferons, Amioderene, Sertraline and Bepridil, Favipiravir, Azithromycin.

Repurposing drugs for Marburg virus infection

Marburg virus disease is known as Marburg haemorrhagic fever. It is closely related to the well-known Ebola virus (EBOV) it is caused by Marburg virus (MARV

Drugs: There is no proper treatment for Marburg virus infection. The drugs which are used for treatment of Ebola viral infection are preferred for the recovery of the patient.

Repurposing drugs for Human Adeno virus infection Table 8

Human Adeno virus infection is caused by human adeno virus ((HAdV). Adeno viruses are group of viruses that cause variety of infections such as respiratory illness, conjunctivitis, croup, bronchiolitis and pneumonia. HAdV exists in seven known HAdV species

The first line adenovirus drugs are: - Cidofovir, Ribavirin

Ongoing clinicaltrial drugs

CMX001 (Brincidofovir), DHEA and epiandrosterone (EA) Analogue, Transition metal complexes, Camptothecin (CPT), Bispecific monoclonal antibodies.

CRediT authorship contribution statement

K. Swathi: Conceptualization, Methodology. B .Nikitha: Writing - original draft. B. Chandrakala: Software, Visualization. K. Laxmanadeviaan: Data curation, Supervision. M. Malleswari: Validation, Writing - review & editing.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Table 2

Disease with mortality rate.

Disease	Mortality rate	Reference
SARS-CoV	~10%	[1]
MERS-CoV	~35%	[1]

Table 3

Drugs Repurposing Drugs of Influenza Virus Infection.

Statins (atorvastatin, Nitazoxanide)	Cholesterol modulators	HMG-Co A reductase inhibitor	Serendipity	Immunomodulator	p-II
nitazoxanide	Anti-parasitic chronic hepatitis	Inhibition of the pyruvate: ferredoxin/ flavodoxinoxidoreductase cycle		HA maturation and transport inhibition	p-III
PPAR antagonists (gemfibrozil)	Antihyperlipidemic	Hepatic glucogenesis inhibitor	Serendipity and phenotypic screening	Immunomodulator	preclinical

Table 4

Repurposing Drugs of Swine Flu.

Infection	Causative organism	Family	Nature of viral genome	Diameter of virus	Shape of virus
CoVID-19	Corona virus	Coronaviridae	Single stranded positive enveloped RNA	60–140 nm	Crown
MERS-CoV	Corona virus(2Cβ)	Coronaviridae	Positive single stranded enveloped RNA	80–160 nM	Crown
SARS-CoV	Corona virus	Coronaviridae	Positive single stranded enveloped RNA	80–160 nM	Crown
Influenza	Influenza A and B	Orthomyxoviridae	Single stranded RNA virus	80–120 nm	Spherical or filamentous
Swine Flu	A(H1N1)	Orthomyxovirus	Single stranded negative RNA virus	80–120 nm	Spherical or ovoid
Hanta Virus Infection	Hanta virus	Hantaviridae	single stranded negative chain RNA virus	80–120 nm	spherical
Zika Virus Infection	Zika virus	Flaviviridae	enveloped, positive, single stranded RNA	Approximately 50 nm	Spherical or icosahedral
Ebola virus infection	Ebola virus	Filoviridae	encapsulated single stranded negative RNA virus	80–14000 nm	Filamentous, hairpin shape
Marburg Virus Infection	Marburg virus	Filoviridae	negative stranded nonsegmented RNA	80 nm-1000 nm	Filamentous, hairpin shape
Human Adeno Virus Infection	Adeno virus	Adenoviridae	Nonenveloped double stranded DNA(36kd)	90–100 nm	icosohedral

Table 6

Zika virus infection is an asymptomatic disease transmitted by mosquitoes.

Acetaminophen	Fever
Antihistamines	Pruritic rashes
Fluids	Prevent dehydration

Table 8

Human Adeno virus infection is caused by human adeno virus ((HAdV) sub groups.

HAvD subgroups	Disease caused	Oncogenicity	Serotype	Reference
A	Urinary	High	12,18,31	[6], [7], [8], [9]
B, type-1	keratoconjunctivitis, urinary	Weakly	3,7,16,21	[6], [7], [8], [9]
B, type-2	Gastrointestinal, respiratory, urinary	Weakly	11, 14, 34, 35	[6], [7], [8], [9]
C	Hepatitis and urinary	Unknown	1,2,5,6	[6], [7], [8], [9]
D	keratoconjunctivitis, gastrointestinal	Unknown	8–10, 13, 15, 17, 19, 20, 22–30, 32, 33, 36–39, 42–49	[6], [7], [8], [9]
E	keratoconjunctivitis, respiratory	Unknown	4	[6], [7], [8], [9]