COVID-19: REPLICATION INHIBITORS AS PROMISING THERAPY FOR SYMPTOMATIC PATIENTSHaghamad Allzain 1, Yassir Hamadalnil 2 1 Assistant Professor in the Department of Biochemistry, Faculty of Medicine, Shendi University, Sudan.2 Department of Clinical Microbiology, Faculty of Medicine, Nile University, Khartoum, Sudan. |
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Received 18 October 2021 Accepted 4 November 2021 Published 30 November 2021 Corresponding Author Haghamad
Allzain, hajamadbulla@yahoo.com. DOI 10.29121/granthaalayah.v9.i11.2021.4337 Funding:
This
research received no specific grant from any funding agency in the public,
commercial, or not-for-profit sectors. Copyright:
© 2021
The Author(s). This is an open access article distributed under the terms of
the Creative Commons Attribution License, which permits unrestricted use, distribution,
and reproduction in any medium, provided the original author and source are
credited. |
ABSTRACT |
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COVID-19
is unprecedented pandemic threading the mankind existence in the recent time,
with globally reported (256,966,237) confirmed cases, including (5,151,643)
death, as of 22 of November 2021WHO (2020). The
COVID-19 vaccine doses administered globally were (7,408,870,760) doses as of
22 of November 2021 WHO (2020). Strategy
to face this serious threat include prevention of getting infection and
rational treatment of symptomatic infected ones. Treatment can adopt one or
all of the three strategies; prohibiting the virus from entry into the human
cells, halt replication of the virus inside the human cells, and neutralizing
the inflammatory and other effects of the virus pathogencity. Replication
inhibitors are important tool in the tools box against COVID-19, however they
are not substitute for vaccination against COVID-19 and other adopted
preventive measurements. Still prevention is the best medicine for any
disease. The aim
of this review is to further explore the replication inhibitors as emerging
tools for treatment of symptomatic cases of COVID-19. Many encouraging
results have emerged from recent clinical trials. This may help to bridge the
gap in existence knowledge and stimulate further discussion to enhance
conducting more clinical trials for the treatment of COVID-19 and repurpose
already existing other viral replicating indictors for treatment of
COVID-19. Remdesivir, Molnupiravir and
Paxlovid are promising viral replicating inhibitors drugs for treatment of
symptomatic COVID-19 patients. Since Molnupiravir and Paxlovid are given orally as five days short
course, are significantly of great value for low-income countries. |
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Keywords: COVID-19,
Coronavirus, Remdesivir, Molnupiravir, Paxlovid 1. INTRODUCTION Coronaviruses belong to
the Coronaviridae family in the order Nidovirales, it possesses a crown-like
spikes on the outer surface of the virus; so, it was named Boopathi
et al. (2020), Coronaviruses
size is (65–125 nm) in diameter and contain a positive sense, single-stranded
RNA as a nucleic material with size ranging from 26 to 32kbs in length Schoeman and Fielding (2019). The subgroups
of coronaviruses family are alpha (α), beta (β), gamma (γ) and
delta (δ) coronavirus. Beta. These viruses were thought to infect only
animals until the world witnessed a severe acute respiratory syndrome (SARS)
outbreak caused by SARS-CoV, 2002 in Guangdong, China. Another pathogenic
coronavirus, known as Middle East respiratory syndrome coronavirus (MERS-CoV)
caused an endemic in Middle Eastern Countries. a decade later Harapan and Itoh.
(2020) |
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Khan et al. (2020). However, beta-coronaviruses are clinically important group because they comprise the most highly pathogenic viruses against humans, including SARS-CoV-2, MERS-CoV, and SARS-CoV Khan et al. (2020), Cui et al. (2019)
2. CORONA VIRUS STRUCTURE
The characteristic morphology of Corona virus is
spherical envelope, with club-shaped projections, that look like solar corona
or a crown and made of a highly glycosylated protein called spike protein. It
has other three structural proteins, envelope, membrane, and nucleocapsid. The virus genome is single strand
positive-sense RNA, that is similar to host mRNA of approximately (26 to 32)
kb. The first two-thirds of the genome consists of two large overlapping open
reading frames that encode sixteen (16) nonstructural proteins, including
proteases, RNA-dependent RNA polymerase (prRdRp), RNA helicase, primase, and
others, that form the viral replicase complex, a platform to propagate viral
mRNAs. The remaining portion of the genome includes interspersed open reading
frames for the structural proteins, as well as a number of accessory proteins
generally nonessential for replication in tissue culture but capable of
suppressing immune responses and enhancing pathogenesis. The nonstructural
proteins are all potential targets for therapies, which would in theory work
against all corona viruses. Bergmann and Silverman (2020).
Symptoms of COVID-19 starts from two days to two weeks after exposure to the virus with mean incubation period of about five (5) days WHO (2020). Presentations of COVID-19 have ranged from asymptomatic, mild symptoms, to severe illness and death. Common symptoms have included fever, cough, and shortness of breath. Other symptoms, such as malaise and respiratory distress, have also been described Lauer et al. (2020), Hui et al. (2020).
Viral
genome replication is essential step in the virus life cycle and it is a
potential site for antiviral intervention, such as chain terminators and other
antiviral drugs acting by inhibiting different steps in the virus life cycle.
The development of effective intervention strategies
relies on the knowledge of molecular and cellular mechanisms of corona virus infections, there is urgent
need to understand why SARS- CoV-2, in contrast to SARS- CoV, is replicating so
efficiently in the upper respiratory tract and which viral and host
determinants are decisive on whether COVID-19 patients will develop mild or
severe disease. Philip V'kovski et al. (2021)
The
unprecedented serious challenge of emergence of HIV virus and AIDS in the
precious century has proved that new medicines to tackle the emerging disease
can be developed. Azidothymidine (Zidovudine or AZT), which inhibit viral
replicase proteins, is used for the treatment of HIV-type1and 2, and most of
the early anti-viral drugs, such as acyclovir, were nucleoside and nucleotide analogues,
Julia et al. (2005)
3. COVID-19; PROMISING REPLICATING INHIBITORS
SARS-CoV-2 replication is associated with a down regulation of host cell protease inhibitors. The protease inhibitor aprotinin inhibited SARS-CoV-2 replication in therapeutically achievable concentrations. Therapeutic aprotinin concentrations exert anti-SARS-CoV-2 activity. Aprotinin is a serine protease inhibitor, which has been shown to inhibit transmembrane serine protease 2 (TMPRSS2) and has been suggested as optional treatment for influenza and corona viruses. Aprotinin aerosol may have potential for the early local control of SARS-CoV-2 replication and the prevention of COVID-19 progression to a severe, systemic disease. Bojkova et al (2020).
Due to the urgent need to control COVID -19 infection pandemic, use of existing antiviral drugs with showed potential inhibiting effects on the replication of coronavirus has been adopted as optional therapeutic tools. Nelfinavir has previously demonstrated antiretroviral activity and used as drug against HIV- type 1. It inhibits the replication of the SARS and SARS-CoV-2-in vitro. It showed potential inhibition against the viral protease such as 3CLpro Norio et al. (2020).
Nucleotide analog drugs can inhibit the viral replication cycle through targeting the viral RNA-dependent RNA polymerase, essential for transcription and replication of RNA genome, such as Favipiravir, which is a guanine analog with activity against many RNA viruses such as SARS-CoV-2 via inhibition the viral RNA-dependent RNA polymerase. It acts as chain terminator. Other drug is Ribavirin and galidesivir, the originally antiviral drugs against the HCV, are able to bind to the RNA-dependent RNA polymerase of SARS-CoV-2 and inhibit the viral RNA synthesis.
Ivermectin is an FDA-approved broad spectrum anti-parasitic agent. Reports suggested that ivermectin's nuclear transport inhibitory activity may be effective against SARS-CoV-2 Leon et al. (2020)
Lumacaftor and Cepharanthine displayed activity in inhibiting helicase Nsp13 ATPase activity of SARS-CoV-2, essential for viral replication and the most conserved nonstructural protein within the corona virus family, promising that these drugs can be potentially considered for the treatment of COVID-19 Mark et al. (2020). All of these drugs are potential candidates to be evaluated in clinical trials and repurposed for treatment of COVID-19.
4. REMDESIVIR (RDV)
The most promising drug is Remdesivir (RDV), monophosphoramidate prodrug with a molecular mass of 602.6 g/mol and chemical formula C27H35N6O8P. It is known as GS-5734, and metabolized into GS-441524, Frediansyaha et al. (2021). It is an adenosine analog, a primary developed drug by Gilead Sciences of Foster City, California, US. in 2017 to treat the Ebola, and has a potential activity against a wide spectrum of single stranded RNA viruses such as SARS-CoV-2, which acts as an RNA-dependent RNA polymerase inhibitor by binding to the viral RNA-dependent RNA polymerase, and hence, it is an RNA-chain terminator. It is effective as dose of (10mg/kg) for twelve (12) days and it is safety in the human is demonstrated by clinical trials. Ghanbari et al. (2020), Yousefi et al. (2020).
Remdesivir was found to be superior to placebo in
shortening the time to recovery in adults who were hospitalized with COVID-19
and had evidence of lowering respiratory tract infection, as suggested by the
results of multi- national clinical trial John et al (2020),ClinicalTrials.gov Identifier NCT04292730 (2021), ClinicalTrials.gov Identifier: NCT04292899 (2020)).
Supported by data from multiple clinical trials, Remdesivir (Veklury) is the first authorized medicine by the European Medicine Agency (EMA) for SARS-COV2 treatment on June 25/2020 EMA (2020). It is also the first drug to win full U.S. Food and Drug Administration (FDA) approval for treating COVID-19, in adult and pediatric patients twelve (12) years of age and older and weighing at least forty (40) kilograms, on October 22/ 2020.Remdesivir should only be administered in healthcare settings capable of providing acute care similar to inpatient hospital care FDA (2020). The adverse reactions known after receiving Remdesivir include gastrointestinal disturbances such as nausea and vomiting, hepatoxicity with elevations of liver enzyme aminotransferase, and infusion related reaction, such as hypotension, and shivering Lam et al. (2020).
5. MOLNUPIRAVIR; THE EXPECTED GAME CHANGER
It is known as (82) Merck bills, a nucleoside analogue, the first oral
antiviral treatment for COVID -19 reporting promising clinical trial data. It
is developed by Merck-
US drug- maker company.
It is originally used to treat influenza. It is designed to introduce errors
into the genetic code of the virus, when incorporated into viral RNA, shifting
its configuration, mimicking the nucleoside cytidine and uridine, causing point
mutation, and where deleterious transition mutations accumulate in viral RNA causing
lethal mutagenesis, which eventually leading to viral population collapse. Malone and Elizabeth (2021).
Campbell. Trial results suggest molnupiravir needs to be taken early
after symptoms develop to have an effect. It can cut hospitalizations
and deaths among people with COVID-19 by half (50%).
The possibility that molnupiravir
could incorporate itself into human DNA, raise safety concerns and need to be
monitored Fischer et al. (2021), Sheahan et al. (2020) Cox et al. (2021).
Molnupiravir
has been approved in United Kingdom by Medicines and Healthcare Products
Regulatory Agency for the treatment of established infections of COVID-19, in
November 2021. Mahase
(2021).
On Friday19 th 2021 EMA. (2020) ;the European
Medicines Agency, which
is the European Union’s drug regulator, approved emergency use of (Molnupiravir) Merck’s
COVID pills for
adults who have tested positive for COVID-19 and it prepares to make a decision
on full approval by the end of the year.
Molnupiravir along with vaccination, will reduce dramatically the burden on the health systems globally, and speed up the ending of the COVID-19 pandemic.
6. PAXLOVID; ANOTHER REAL GAME-CHANGER
Paxlovid
oral bills, developed by Pfizer; US pharmaceutical company contain two
components: PF-07321332 and ritonavir. PF-07321332 is protease inhibitor, blocking 3CL protease ;
3C-like protease, an endopeptidase, is the main cysteine protease found in coronaviruses. It
cleaves the virus polyprotein at
eleven conserved sites. 3CL protease inhibitors prevent viral replication by
selectively binding to viral proteases and
blocking proteolytic cleavage of protein precursors that are necessary for the
production of infectious viral particles.
Protease inhibitors have been
used for the treatment of HIV and hepatitis C.
Ritonavir prevents cytochrome
enzymes from destroying
PF-07321332. Ritonavir plays the same defensive role in antiviral drug cocktails for HIV treatment. Paxlovid oral bills
are given every twelve (12).
hours for five days.It reduces the risk of hospitalization by eighty nine percent ( 89%). Less than one percent (1%) of patients taking the drug
needed to be hospitalized and no death reported in the active group compared to
seven percent (7%)
hospitalization and ten (10)
death, which was about (1.6%)
in the placebo group, out of seven hundred and seventy-five (775) adult participant in the
clinical trial, as the company announced that on Friday, 5th of November, 2021.It is obviously
more effective than Molnupiravir of Merck Company. The side effects of the drugs were mild and
reported in about nineteen percent (19%) versus twenty one percent (21%) in the placebo
group. Mahase
(2021).
The Molnupiravir and
Paxlovid are
expected to be approved and available for COVID-19 patients in most countries
before the end of this year 2021.
The challenge faces antiviral therapy is the unpleasant side effects, as well as financial cost. There is urgent need to develop more safe, tolerable and efficacious drugs, with lesser side effects Julia et al. (2005).
7. DISCLAIMER
The information in this review should not be used for diagnosis and treatment of individuals’ problems or in place of a consultation with competent health care professionals.
The author and publisher disclaim all responsibility for any errors or harms occur as the results obtained from use of the information contained in this review.
AUTHOR CONTRIBUTIONS
All authors have contributed significantly to conceptualization of the idea, writing the original draft preparation reviewing and editing. All authors have read and agreed to the published version of the manuscript.
CONFLICTS OF INTEREST
All authors have no conflicts of interest to declare. All authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in the manuscript.
ABBREVIATIONS
DNA; Dexoyribonucleic Acid, RNA; Ribonucleic Acid. EMA; European medicine Agency. EUA; Emergency Use Authorization. FAD; Food and Drugs Administration, CDC; Centers for Disease Control and Prevention. Kb; Kilo base.
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