In this presentation you will find everything you need to know about the antiviral drug Remdesivir. It was made by pharmaceutical student, for medicinal chemistry course. Hope you enjoy it and leave a like.

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2. OUTLINE
COVID19
Overview
Treatment
Suggestions
Remdevisir References
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• Drug History and
Development.
• FDA approval, comments.
• Therapeutic uses.
• MOA.
• Metabolism pathways.
• Drug-Target intermolecular
interaction.

3. COVID19 OVERVIEW
 The novel coronavirus or COVID19 is a new infectious disease that attack the respiratory
system and cause pneumonia; was primary identified as an unknown etiology.
The virus also have the ability to affect the neurological,
enteric and hepatic systems.
It affected almost 13 million people world wide*.
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*: until 13th of July 2020

4. COVID19 OVERVIEW
Structurally, it is a ssRNA virus, associated with a nucleoprotein
within a capsid comprised of matrix protein.
The envelope bears club-shaped glycoprotein projections.
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5. TREATMENT SUGGESTIONS
Ever since the pandemic started, every pharmaceutical company has been working hard to
be the first to find a cure, treatment or a vaccine.
Over 500 clinical trials have been registered to the FDA; RCTs have been done on many
agents including
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Lopinavir–
ritonavir
Favipiravir HCQ
(monotherapy
and with
Azithromycin)
IL6
Inhibitors
Blood
Transfusion
Stem-cells
transplantation
Remdesivir

6. HISTORY AND DEVELOPMENT OF REMDESIVIR
RDV was developed in 2009
by Gilead Sciences and with
the help of CDC1 and
USAMRIID2.
They started the work to find
a treatment for EBOV; which
is an RNA based virus.
Also SARS and MERS. Which
come from the same
Coronavirdae family.
The drug is a modified
nucleotide prodrug, which
helps it to penetrate the cell
membrane.
So, the drug was already
known to be effective
against the SARS-CoV-2
before the outbreak.
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 During this time it has been tested among different agents for the effectivity and was found that it had the
lowest EC50
1: Center for Disease Control and Prevention
2: US- army medical Research Institute of infectious diseases

7. FDA POINT OF VIEW
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1: National Institution of allergy and infectious diseases.
2: Severe disease is defined as patients with low blood oxygen levels or needing oxygen
therapy or more intensive breathing support such as a mechanical ventilator.
On 26th Feb 2020, they initiated two phase 3 trials of RDV on severe COVID19 patients. And On April 29th
the drug has shown positive data according to NIAID1 study’s.
On May 1st ,the FDA has issued an emergency use authorization EUA for the investigational antiviral drug
Remdesivir, for the treatment of suspected and positively tested COVID19 in adults and children with
severe disease2.
The drug has shown to decrease the recovery time of COVID19 patients; the use is still limited since there
is no adequate information on the safety and effectiveness of it.
The emergency use authorization allows for remdesivir to be distributed in the U.S. and administered
intravenously by health care providers.

8. THERAPEUTIC USES
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RDV was previously tested as
an Ebola treatment.
It has generated promising
results in animal studies for
MERS and SARS.
Severe COVID19 patients.

9. MECHANISM OF ACTION
To start understanding how RDV works, it is very important to understand the underlying
infection and how it happens.
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o The spikes (protein S)1 bind to ACE-2 receptor on
host cell membrane and the virus enters the cell by
endocytosis2 .
o When the ssRNA of virus reach the cytoplasm of cell
the RdRp start to produce new strands of RNA;
Which result in producing more viruses
o And here comes the role of Remdesivir.
1: are proteins found on viruses surfaces
2: The process by which substances are brought into the cells.
FIG.1

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RDV is an antiviral
prodrug of the active
drug GS-441524 (C-
adenosine) targeting
the viral genome
replication process
and inhibit it.
It enters the infected
cell and is
metabolised to its
active form GS-
441524 adenosine
TP1 which binds to
RdRp2.
RdRp will be confused
thinking that GS-
441524 is adinosine
TP and will
incorporate it to the
RNA strand of the
virus
The resulted RNA is
defective and leads to
premature
termination of RNA
synthesis.
FIG.2
1: Triphosphate
2: RNA-depolarizing-RNA-polymerase
MECHANISM OF ACTION

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Although COVID-19 have a proofreading process 3’5’-exoribonuclease-
EXO-N, that is able to detect and remove other nucleotide analogous
but we can come over this problem by increasing the dose of
Remdesivir .
Remdesivir is classified as a delayed chain terminator as its induction,
an irreversible chain termination, is not immediate, but the RNA chain
termination takes place after an additional five nucleobases are
incorporated into an RNA chain that is being synthesized.
MECHANISM OF ACTION

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Potential resistance to remdesivir was already identified
that would make its therapeutic use less effective.
However, resistance to remdesivir is overcome with
increased but nontoxic concentrations of this nucleotide
analog.
MECHANISM OF ACTION

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DRUG-TARGET INTERMOLECULAR INTERACTIONS
An important feature which makes RDV differ
from adenosine is the change of one
particular chemical bond on the molecule.
Rather than a bond linking a carbon and
nitrogen atoms, chemists replaced the
nitrogen with another carbon, creating a C-C
bond.
This is critical to the success of this drug
because COVID19 have a special enzyme that
recognizes unnatural nucleosides and clips
them out.
But by changing this chemical bond, RDV
cannot be removed by the enzyme, allowing
it to stay in the growing chain and block
replication.
FIG.5 a
FIG.5 b

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DRUG-TARGET INTERMOLECULAR INTERACTIONS
Remdesivir (GS-5734) is a 1′-cyano-substituted adenosine
nucleotide analogue prodrug that shows broad-spectrum
antiviral activity against several RNA viruses (discussed
earlier).
The chemical structure of RDV contains the
following
1. Amido substituent of the phosphoric acid
moiety
2. Phenyl substituent of the phosphoric acid
moiety
3. Cyano (-CΞN) group at carbon 1 of the
ribose sugar
4. Modified nucleobase of RDV
5. Active nucleoside of GS-441524
 1 and 2 should be removed during the
drug’s activation
 The cyano group is not removed as it has an
important contribution to the overall activity
 5 requires phosphorylation to its
triphosphate to exhibit its activity
5FIG.4

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FIG.5
DRUG-TARGET INTERMOLECULAR INTERACTIONS
FIG. 5 shows the structure of the active
metabolite GS-445124
The binding of GS-441524; Based on PDB1
and the FMO2, occurs as following
There are five binding residues of Remdesivir
on the RdRp; Lys545, Arg555, Ser682, Asn691
and Asp766.
Lys545 was electrostatically repulsive and
Arg555 was situated distantly, their
contribution were negligible
Ser682 formed hydrogen bond with +1U of the
complementary strand
From the perspective of steric confirmation,
the drug binds to the structure of 7BV23 by
three hydrogen bonds (two with +1U’ and one
with the adjacent intra-structural -1U)
The sugar portion  1-Cyano- moiety binds to
Thr687, -OH on the sugar portion binds to
Asn691
Asp760 binds via electrostatic properties to
the drug 1: Protein Data Bank
2: Fragment molecular orbital method
3: nsp12-nsp8-nsp7 complex

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DRUG-TARGET INTERMOLECULAR INTERACTIONS
This figure shows the structure that was used in the FMO calculation
a) The 7BV2 complex and RDV is shown in an atomic colors
b) Magnified image of RDV surrounding structure on RNA side
c) RdRp side
 The atomic colors are  C: gray, O: red, N: blue, P:pink, and H: white
FIG. 6

17. PHARMACOKINETIC OF RDV
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The drug is given via an IV administration, it is available as lyophilized powders and concentrated solution.
• The recommended loading dose for adults and children (wt. >=40Kg) is 200 mg on day 1 and the maintenance dose is 100mg on day 2.
• The loading dose for pediatric (wt. >=3.5-40 Kg) is 5mg/Kg and the maintenance dose is 2.5mg/Kg
The drug is almost distributed to all tissues
The PPB for RDV is moderate, while the active metabolite has low binding ability
The Mwt. of the RDV is 602.585 Dalton (showed EC50 of 460 ng/mL), and for GS-441524 is 291.3 Dalton.

18. One study on rats showed that RDV is metabolized extensively by CYP450 enzymes, there was no
detectable metabolism of it by recombinant CYP1A2, CYP2B6, CYP2C9, or CYP2C19.
It was metabolized by CYP2C8, CYP2D6, and CYP3A4.
Metabolism data on intermediate metabolite GS-704277, the nucleoside metabolite GS-441524
and the pharmacologically active analog of adenosine triphosphate GS-443902 has not been
reported. 18
FIG.7
PHARMACOKINETIC OF RDV
Intracellular processing of the prodrug remdesivir ,
and the possible metabolism pathway.

19. The half-lives are about 69 min and 25 h for
remdesivir and GS-441524, respectively.
Remdesivir is mainly excreted in urine about
74%, the predominant species detected in urine
were GS-441524, followed by remdesivir and
other metabolites.
The optimal duration of treatment is still
unknown.
The drug is associated with some side effects
and the most important one is transaminitis
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PHARMACOKINETIC OF RDV

20. REFERNCES
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https://www.fda.gov/news-events/press-announcements/coronavirus-
covid-19-update-fda-issues-emergency-use-authorization-potential-covid-
19-treatment
https://www.gilead.com/purpose/advancing-global-health/covid-
19/remdesivir-clinical-trials
https://www.fda.gov/media/137566/download
https://chemrxiv.org/articles/Intermolecular_Interaction_Among_Remdesi
vir_RNA_and_RNA-Dependent_RNA_Polymerase_of_SARS-CoV-
2_Analyzed_by_Fragment_Molecular_Orbital_Calculation/12362222/1?fil
e=22782881
https://www.ema.europa.eu/en/documents/other/summary-
compassionate-use-remdesivir-gilead_en.pdf
https://pubs.acs.org/doi/pdf/10.1021/acscentsci.0c00489

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