Potential use of RNA-dependent RNA polymerase (RdRp) inhibitor against

COVID-19 infection

Charles NS Allen 1, ‡, Sterling P Arjona 1, ‡, Maryline Santerre 1, Bassel E Sawaya 1, 2, ¶

1 Molecular Studies of Neurodegenerative Diseases Lab, FELS Institute, 2 Department of Neurology; Lewis Katz
School of Medicine - Temple University Philadelphia, PA 19140.

‡ Charles NS Allen and Sterling P Arjona contributed equally to this work. Author order was determined
alphabetically.

¶ Corresponding Author:
Bassel E Sawaya, PhD, MS(IME), MBA,
Fels Institute for Cancer Research,
Lewis Katz School of Medicine,
Temple University.
3307 North Broad Street;
Philadelphia, Pennsylvania 19140.
Phone: 215-707-5446;
Fax: 215-707-5948;
E-mail: sawaya@temple.edu
ABSTRACT

Favipiravir, an inhibitor of RNA-dependent RNA polymerase used against the Japanese flu, was

recently suggested as a potential COVID-19 inhibitor. Since Favipiravir targets a critical and a viral

specific process, using it as a treatment could be beneficial in slowing the outbreak. Though there have

been many suggested antivirals to treat SARS-CoV-2 infection, most treatments target host-associated

pathways that may cause adverse effects, Favipiravir or similar combination may be the best remedy

against COVID-19 pandemic.

INTRODUCTION

Coronavirus Disease-2019 (COVID-19) is the disease caused by the novel severe acute respiratory

syndrome-coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a member of the coronavirus family recently

discovered in Wuhan, Hubei, China. The coronavirus family was initially discovered in the later part of

the 1960s. Since the discovery there have been several members of this virus that have caused serious

respiratory tract infections, these include Severe Acute Respiratory Syndrome (SARS-CoV) in 2003,

Middle East Respiratory Syndrome (MERS-CoV) in 2012, and the current outbreak SARS-CoV-2

(previously known as 2019-nCoV).

Coronaviruses (CoVs) belong to the Nidovirales order and got their names from the unique “crown-

like” spikes that are visible on the outer membrane of the virions. Coronaviruses are large single-

stranded, enveloped RNA viruses that are broken down into four classes: Alphacoronavirus,

Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. Coronaviruses are the largest RNA

viruses known with a genome ranging between 27 and 32 kb (1). Like all the Nidovirales members,

Coronaviruses have a highly conserved genomic organization, unique enzymatic activities, and

expression of nonstructural genes by ribosomal frameshifting.

Since the initial infection of SARS-CoV-2 in Wuhan the virus has spread globally. Although the

mortality rate of COVID-19 is comparatively lower than previous coronavirus outbreaks (SARS-CoV-

10% and MERS-CoV- 37%), it is much higher than the 2018-2019 influenza season (0.96%). The first

case in the United States was confirmed on January 20, 2020 in Washington State and has since spread

to every states and territories. This outbreak has been devastating to older population (over 60) which

are at higher risk and show more severe symptoms when compared with younger population. As with

other coronaviruses, SARS-CoV-2 infects the lung epithelial cells of the alveola and can lead to severe

complications including pneumonia (2). COVID-19 has caused a global shut down of commerce and

normalcy with governments calling for social distancing and even lockdown of entire cities and

countries. It is thus important for the discovery of treatments for this novel virus to slow the outbreak

and shorten the disease.

VIRAL COMPONENTS AND LIFE CYCLE

 SARS-CoV-2 is an enveloped single-stranded positive-sense RNA virus composed of four structural

proteins, envelope (E), membrane (M), spike (S), and nuclear capsid (N) (3) (Figure 1). In addition to

the structural proteins, the genome contains a 5’ cap structure along with a 3’ poly (A) tail that a cts as

a mRNA for translation of the replicase polyproteins. The replicase gene encodes the nonstructural

proteins (NSPS) that form two-thirds of the genome. The genome also include several accessory

proteins that are not essential for viral replication but were shown to play a role in viral pathogenesis.

Even though, the E protein is not conserved between coronaviruses, however it is important for

assembly and release of the virus. The M protein gives the virion its spherical shape and is the most

abundant protein. The S protein has been shown to be important in host cell interactions and virulence

(4). The N protein binds to the single-strand RNA inside the capsid to protect it in a beads-on-a-string

conformation. SARS-CoV-2 differs from other coronaviruses because of its S protein. The S1 domain

of the S protein has been shown to have a 45% difference in the amino acid sequence compared to

that of SARS-CoV.

It has been found that the virus enters the body via droplets that travel to the respiratory tract, where

it can infect cells containing angiotensin-converting enzyme 2 (ACE2) including lung epithelial cells (5).

The S1 domain of the S protein has been shown to interact with ACE2 on the surface of cells (4). The

S protein has also been predicted to interact with the Glucose Regulated Protein 78 (GRP78) (6). After

binding to a receptor on the cell surface, the S protein is cleaved by a cellular protease : cathepsin (7)

or TMPRSS2 (8) to expose the fusion peptide allowing the viral membrane to fuse with the cellular

membrane. The viral genome is then released into the cytoplasm. Next, the host ribosomes translate

the viral positive-sense RNA into 16 non-structural proteins (NSPS) (Table 1) (3). Some of these NSPS

are involved in ensuring viral RNA is translated efficiently without host interference. Other NSPS are

important for producing mature virions. The rest of the NSPS make the replicase-transcriptase complex

(RTC). The RTC is composed of proteins that are required to replicate viral RNA both genomic and sub-

genomic through anti-sense RNA intermediates (3).

After viral genomic RNA replication and viral protein translation from sub-genomic RNA, the viral

structural proteins are inserted into the endoplasmic reticulum (ER). After this insertion, the proteins
follow the secretory pathway and form the endoplasmic reticulum-Golgi intermediate compartment

(ERGIC) (8). Once the ERGIC is formed the viral RNA genomes, which are encapsulated by the N

protein, are incorporated into the ERGIC which then buds into mature virions. The mature virions exit

the cell via exocytosis and can infect other cells or be spread to other hosts.

VIRAL RNA REPLICATION AS A THERAPEUTIC TARGET

Currently, clinicians can only treat the various symptoms of COVID-19 because there is no targeted

treatment for the SARS-CoV-2. Nevertheless, drugs used to treat Malaria and HIV-1 such as

Chloroquine and Lopinavir/ritonavir, respectively, have been shown to possibly influence SARS-CoV-2

replication. Table 2 summarizes all the potential drugs that are in stage of development and the names

of the pharmaceutical companies developing these drugs. Additional companies and schools launched

studies aiming to develop new COVID-19 drugs/vaccine such as Pfizer, Enata Pharmaceutical, Integral

Molecular, Takeda Pharmaceutical Company, Hong Kong University of Science and Technology,

Columbia University, Tulane University and others (clinicaltrialsarena.com/ analysis/coronavirus-mers-

cov-drugs/).

Chloroquine has been shown to inhibit the glycosylation of ACE2 and thus prevent SARS-CoV-2

from binding to cells. Studies revealed no cytotoxicity in vitro, however the glycosylation of ACE2 is

important in the regulation of the renin-angiotensin system (9). Deregulation of this system could cause

some adverse effects.

Similarly, Lopinavir/ritonavir is a protease inhibitor that could block the cleavage of the S protein of

SARS-CoV-2 thus preventing fusion of the viral and cellular membranes (10). However, there are many

known adverse effects of this drug and it has shown no significant improvements over standard care in

treating COVID-19.

Ideally, it is better to target a step of the virus life cycle preventing it from forming mature virions and

infecting other cells without damaging host cell function that could cause adverse side-effects. In order

to reduce adverse effects, viral-specific processes can be inhibited or reversed. SARS-CoV-2 relies on

host cellular mechanisms to reproduce mature virions. However, RNA replication from an RNA template

is unique to the virus thus making this step a possible therapeutic target. Inhibiting the virus at the RNA
replication step would result in 1) no genomic RNA replication, 2) no subgenomic replication and

subsequent structural protein production, and 3) no mature virion formation and release essentially

stopping the productive infection. By only targeting the RNA replication of the virus, NSPS can still be

produced at low levels inside the cell but infection would end there. A possible drug candidate that

inhibits the RNA-dependent RNA polymerase (RdRp) and would result in the inhibition of SARS-CoV-

2 is Favipiravir.

FAVIPIRAVIR

Favipiravir (6-fluoro-3-hydroxy-2-pyrazinecarboxamide) also known as T-705, Avigan or Favilavir,

is an antiviral agent that was first developed by Toyama Chemical Co. against the Japanese flu (11).

Favipiravir is a pyrazinecarboxamide derivative that can inhibit the RdRp of influenza virus and was

also shown to have antiviral activities beyond Japanese flu. In animals, Favipiravir has shown activity

against viruses such as Influenza, West Nile, Yellow fever, Foot and Mouth Disease, and Rift Valley as

well as other Flaviviruses, Arenaviruses, Bunyaviruses, Alphaviruses (e.g. Chikungunya [CHIKV];

Sindbis [SINV]; Western equine encephalitis [WEEV]; and Semliki Forest [SFV] viruses), and

Enteroviruses (12-14). Favipiravir was also shown to have an effect in vitro and in vivo against Zaire

Ebola (15), Rabies (RABV) (16) and Zika viruses (17). Favipiravir was escribed to reduce the morbidity

and mortality associated with RABV infection in mice. In Syrian hamster model that mirrors the human

disease, Favipiravir reduced encephalitis, hemorrhagic fever, respiratory difficulties and mortality rate

caused by Nipah virus infection (a Bat virus) (18).

Favipiravir is structurally similar to Ribavirin (antiviral drug used to treat Respiratory Syncytial Virus

[RSV] infection, Hepatitis C and some viral hemorrhagic fevers) (19). Favipiravir and Ribavirin share a

carboxamide (C-[O]-NH2) moiety, however Favipiravir is a more specific version of Ribavirin. Both drugs

target the viral RNA polymerase, Ribavirin primarily targets the Inosine-5′-monophosphate

dehydrogenase (IMPDH), while Favipiravir interacts with RNA polymerase.

Mechanistically, Favipiravir and its form Favipiravir-RMP (favipiravir-ribofuranosyl-50-

monophosphate) do not inhibit influenza RNA polymerase activity, but it is the phosphoribosylated form,

favipiravir-ribofuranosyl-50-triphosphate (Favipiravir-RTP) that inhibits the enzyme. It has been

suggested that the human hypoxanthine guanine phosphoribosyl-transferase (HGPRT) plays a role in

the Favipiravir activation (20). The active form of Favipiravir is recognized by the catalytic domain of the

viral RNA-dependent RNA polymerase and blocks its enzymatic activity. This results in inhibition of the

RNA-dependent RNA polymerase and effectively ending the infectious cycle of SARS-CoV-2 (Figure

2). Note that Favipiravir is not toxic to mammalian cells and does not inhibit RNA or DNA synthesis

within these cells.

All these features make Favipiravir a broad-spectrum inhibitor of RdRp, the polymerase responsible

for replicating RNA and the major functional unit of the RTC in SARS-CoV2 making this drug the best

available drug to fight the spread of COVID-19.

Currently, Favipiravir has been approved in Japan as an influenza treatment (Japanese flu), while

awaiting approval in the USA after successfully passing phase III clinical trials. Favipiravir has been

shown to be an efficient treatment against COVID-19 in Wuhan, China . Even though, the study lacks

controls (double blinded, placebo), however Favipiravir has been shown to reduce viral clearance time

in 80 patients to 4 days compared to 11 days for the control group, and that 91.43% of patients had

improved CT scans with few side effect. These results encouraged other countries such as Turkey to

start using Favipiravir as a potential treatment against COVID-19.

CONCLUSION AND FUTURE DIRECTIONS

COVID-19 caused by the novel coronavirus, SARS-CoV-2, is currently spreading quickly across the

globe. Favipiravir is an ideal targeted treatment since it is viral-specific and has already been used in

clinical trials including a Phase 3 trial for the treatment of Japanese influenza. Favipiravir targets and

blocks viral RNA-dependent RNA polymerase (RdRp) that is used by the virus to replicate and produce

mature virions. Blocking this step in the viral life cycle won’t prevent infection but will shorten the duration

and reduce the severity. It may also shorten the time a patient is contagious. Clinical trials need to be

completed to further explore the possibility of Favipiravir as an effective treatment for the spread and

severity of SARS-CoV-2, but the previous research seems promising that Favipiravir could be a useful

treatment.
 In conclusion, Favipiravir has great potential to be effective in treating COVID-19 and should be

fast-tracked into clinical trials in the US. A drug like Favipiravir that can shorten infection will help to

reduce the number of fatalities that SARS-CoV-2 is estimated to cause in the near future.

ACKNOWLEDGMENTS

This work is supported by an NIH-NIA (R01-AG054411) awarded to BES.

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FIGURES LEGENDS

Figure 1. Schematic presentation of the COVID-19 structure. Structural Proteins of SARS-CoV 2

where the location and names of the viral proteins are shown (S= spike; N= nucleocapside; M=

membrane; E= Envelope). Structure was created using Biorender software.

Figure 2. Favipiravir Mechanism of Action. Numbers in black indicate the normal life cycle of SARS-

CoV2 from 1) binding to ACE2 receptors and then fusion with the cellular membrane, 2) release of the

viral genome in the form of (+) sense RNA and the subsequent production of non-structural proteins

(NSPS), 3) translation and formation of the replicase-transcriptase complex (RTC), 4) RNA replication

of genomic and subgenomic RNA, 5) transcription of subgenomic RNA, 6) translation of that RNA into

structural proteins, 7) nucleocapsid combination with S, E, and M proteins in the ERGIC, 8) budding of

the ERGIC into a mature virion, and 9) exocytosis of mature virions. Numbers in red indicate the

mechanism of action of Favipiravir from 1) entry into the cell in the inactive form, 2) converted to active

form by phosphoribosylation, and 3) binding to RNA-dependent RNA polymerase to block its active site.

Table 1. List of viral NSPS and their known functions.

Table 2. List of Potential or in development drugs, pharmaceutical companies and mechanisms

of action. Yellow shaded- drugs developed to treat different diseases but was used to treat COVID-19;

White shaded- names of major drugs/vaccine that have the potential to become drugs in various stage

of development; Light Green shaded- drugs in various stages of development globally.

FIGURE 1

FIGURE 2
TABLE 1

Protein Function(s)
nsp1 Causes degradation of Host cell mRNA
nsp2 Function currently unknown
nsp3 Multi-domain transmembrane protein which interacts with the viral N protein, promotes
cytokine expression, cleaves viral polypeptides, and blocks host innate immunity
nsp4 Transmembrane protein that is important for double-membrane vesicle (DMV) formation
nsp5 Cleaves viral polyproteins
nsp6 Transmembrane protein
nsp7 One part of the RNA polymerase clamp
nsp8 One part of the RNA polymerase clamp, possible primase
nsp9 RNA binding protein
nsp10 nsp14 and nsp16 cofactor
nsp11 Function currently unknown
nsp12 RNA dependent RNA polymerase
nsp13 RNA helicase
nsp14 MTase and exoribonuclease
nsp15 Viral endoribonuclease
nsp16 Protects viral RNA
TABLE 2

Name Company Targets/Mechanisms

Chloroquine SANOFI Malaria /Arthritis
Favipiravir Toyama Chemical Japanese Flu
TJM2 I-Mab Biopharma Targets GM-CSF (responsible for acute or chronic
inflammation)
No name Medicago and Laval Virus-Like Particles (VLP) of the coronavirus
University’s Infectious Disease
Research Centre
AT-100 (rhSP-D) Airway Therapeutics / NIH Reduces inflammation and infection in the lungs; Generates
an immune response against various respiratory diseases
TZLS-501 Tiziana Life Sciences Anti-interleukin-6 receptor;
Prevents lung damage and elevated levels of IL-6
OYA1 OyaGen Prevents viral replication in cell culture
BPI-002 BeyondSpring Small molecule, activates CD4+ helper T cells and CD8+
cytotoxic T cells;
Generates an immune response in the body
Intranasal vaccine Altimmune Similar to NasoVAX, an influenza vaccine
INO-4800 Inovio Pharmaceuticals/ Activates immune system to generate a robust targeted T
Beijing Advaccine cell and antibody response
Biotechnology
NP-120 (Ifenprodil) Algernon Pharmaceuticals N-methyl-d-aspartate (NDMA) receptor
Glutamate receptor antagonist
mRNA-1273 vaccine Moderna and Vaccine Targets the Spike (S) protein of the coronavirus
Research Center-NIAID
APN01 University of British Columbia Targets ACE2 in SARS
and APEIRON Biologics
Avian Coronavirus MIGAL Research Institute Treats avian coronavirus;
Infectious Bronchitis Modified to treat COVID-19
Virus (IBV) vaccine
TNX-1800 Tonix Pharmaceuticals and Modified Horsepox virus designed to express a protein
Southern Research derived from the virus that causes the coronavirus infection
Brilacidin Innovation Pharmaceuticals Antibacterial, anti-inflammatory and immunomodulatory
properties
Oral recombinant Vaxart No Info
vaccine
Recombinant subunit Clover Biopharmaceuticals Targets the trimeric S protein (S-Trimer) of the COVID-19
vaccine (responsible for binding with the host cell and causing a viral
infection)
Leronlimab (PRO 140) CytoDyn CCR5 antagonist
Linear DNA Vaccine Applied DNA Sciences and No Info
Takis Biotech
BXT-25 BIOXYTRAN Supplies oxygen to the vital organs
MERS vaccine Novavax Binds to the major surface S-protein
AmnioBoost Lattice Biologics Reduces the production of pro-inflammatory cytokines while
boosting the production of anti-inflammatory cytokines
SNG001 Synairgen Research An interferon-β, which is delivered directly to the lungs to
reduce the infection
REGN3048/51 and Regeneron Both antibodies bind to S-protein of MERS coronavirus;
Kevzara Kevzara blocks interleukin-6 pathway
Galidesivir (BCX4430) Biocryst Pharma Nucleoside RNA polymerase inhibitor
Actemra Roche Prevents cytokine storms or overreaction of the immune
system
Remdesivir (GS-5734) Gilead Sciences Developed against Ebola but ineffective