On November 4, 2021, the Medicines and Healthcare Products Regulatory Agency (MHRA) granted marketing approval for Molnupiravir (trade name: Lagevrio), an oral COVID-19 drug co-developed by Merck and Ridgeback, for the treatment of patients with mild to moderate COVID-19. This is the first oral antiviral drug approved globally for the treatment of mild to moderate COVID-19 in adults.

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Paxlovid and Molnupiravir: What Are The
Differences?
On November 4, 2021, the Medicines and Healthcare Products Regulatory
Agency (MHRA) granted marketing approval for Molnupiravir (trade name:
Lagevrio), an oral COVID-19 drug co-developed by Merck and Ridgeback, for
the treatment of patients with mild to moderate COVID-19. This is the first oral
antiviral drug approved globally for the treatment of mild to moderate
COVID-19 in adults.
Clinical data showed that 775 patients recently infected with COVID-19 were
treated with molnupiravir or placebo, respectively. There were 7.3%
hospitalizations and no patient deaths in the molnupiravir-treated group and
14.1% hospitalizations and 8 deaths in the placebo group, p=0.0012. The risk
of hospitalization and death was reduced by 50% in the molnupiravir-treated
group compared to the placebo group. [1]
It is important to note that Molnupiravir must be taken within five days of the
onset of symptoms of viral infection, and is not effective if the patient is already
hospitalized. In addition, patients with mild to moderate COVID-19 taking
Molnupiravir should also include at least one of the following risk factors: e.g.,
obesity, old age, diabetes, or heart disease.
Just one day later, on November 5, 2021, Pfizer made an announcement
that PAXLOVID (PF-07321332; ritonavir), Pfizer's proprietary COVID-19 oral
drug, met the primary study endpoint. The risk of death and hospitalization was
reduced by 89% in the PAXLOVID treatment group compared to the placebo
control group.
This announcement is based on an interim analysis of the Phase 2/3 EPIC-HR
(Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients)
randomized, double- blind study of non-hospitalized adult patients with
COVID-19, who are at high risk of progressing to severe illness.
The scheduled interim analysis showed that 0.8% of patients treated with
PAXLOVID were hospitalized within day 28 after randomization grouping
(3/389 hospitalizations, no patient deaths), compared with 7.0% of patients
treated with placebo who were hospitalized or died (27/385 hospitalizations, 7
deaths). The statistical significance of these results was high (p<0.0001).
A similar reduction in hospitalizations or deaths associated with COVID-19
was observed in patients treated with PAXLOVID within five days of symptom

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onset. 1.0% of patients randomized to PAXLOVID were hospitalized within day
28 (6/607 hospitalizations, no deaths) compared to 6.7% of patients treated
with placebo (41/612 hospitalizations, 10 subsequent deaths), which was
highly statistically significant (p<0.0001). In the entire study population, no
deaths were reported in patients treated with PAXLOVID through day 28. In
contrast, there were 10 (1.6%) deaths in patients taking placebo [2].
From the above data, we can roughly see that Pfizer's Paxlovid seems to have
better efficacy than Merck's Molnupiravir. So are there any differences in the
development mechanism of these two drugs?
How The Coronavirus Infects Cells?
Coronaviruses (SARS-CoV-2) are enveloped viruses that contain a positive,
single-stranded RNA genome, which is packaged within a capsid. The capsid
consists of the nucleocapsid protein N and this is further surrounded by a
membrane, that contains three proteins: the membrane protein (M) and the
envelope protein (E), which are involved in the virus budding process, and the
spike glycoprotein (S), which is a key player in binding host receptor and
mediating membrane fusion and virus entry into host cells.
Structure of COVID-19 Virus
Following, let's us find the mechanism of COVID-19 entry and viral replication
and viral RNA packing in the human cell[3].

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(a) The S-protein on the surface of the virus binds to the ACE2
(angiotensin-converting enzyme 2) receptor in human lung cells, allowing entry
of the coronavirus into human cells through endocytosis (membrane fusion).
(b) After the virus enters the cytoplasm, the proteasome of the human cell
hydrolyzes the S-protein, further activating membrane fusion in vivo.
(c) The proteasome hydrolyzes the viral nucleocapsid protein and the viral
genetic material, single-stranded RNA, is completely released into the
cytoplasm.
(d) RNA is translated into polypeptide chains with the help of ribosomes and
hydrolyzed into RNA-dependent RNA polymerase (RdRp) by 3CLpro enzyme
(3 (a) RdRp uses the genome as a template to generate full-length
negative-sense RNA, which subsequently serves as a template to generate
additional full-length genomes.
(e) Viral membrane proteins, S-proteins and envelope proteins are
synthesized in the cytoplasm and then inserted into the endoplasmic reticulum
and transferred to the Golgi intermediate compartment of the endoplasmic
reticulum.
(f) In the cytoplasm, nucleocapsids are formed by capsidization of replicating
genomes by nucleocapsid proteins, which then aggregate within the
endoplasmic reticulum-Golgi intermediate compartment membrane to
self-assemble into new viral particles.
(g) Finally, the new viral particles are transported to the cell membrane via
smooth-walled vesicles, which are then secreted via exocytosis and thus
exported from the infected cell, thereby infecting other cells. At the same time,
the virus generates pressure on the endoplasmic reticulum eventually leading
to cell death.

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The schematic diagram of the mechanism of COVID-19 entry and viral
replication and viral RNA packing in the human cell.
Treatment Strategies for COVID-19
From the process of entry of the coronavirus into human cells and some
historical experience with coronaviruses, we can broadly derive the following
ways to block the replication of the virus and treat COVID-19.
(1) Direct attack on the S-protein target of the virus with the help of monoclonal
antibodies or plasma from recovered patients, which is also the mechanism of
action of the vaccine, keeping the virus completely out of human cells.
(2)At the cellular level, the transmembrane protease serine 2 (TMPRSS2)
preemptively contacts the S-protein of coronaviruses and promotes viral entry
and infection, so TMPRSS2 would be a potential target for drug development
to inhibit COVID-19. TMPRSS2 inhibitors, such as camostat mesylate, are
considered to be potential antiviral agents against COVID-19. Several clinical
trials of camostat mesylate for the treatment of COVID-19 have been carried
out. The results of one randomized controlled trial showed no improvement in
clinicals [4].
(3)Chloroquine (CQ) and hydroxychloroquine (HCQ) have demonstrated
positive results indicating a potential antiviral role against SARS-CoV-2 （HCQ
is preferred due to its higher water solubility, lower toxicity and also feasibility
for prolonged use with increased tolerance）. Its mechanism of action (MOA)
includes the interference in the endocytic pathway, blockade of sialic acid
receptors, restriction of pH mediated spike (S) protein cleavage at the

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angiotensin-converting enzyme 2 (ACE2) binding site and prevention of
cytokine storm. Unfortunately, its adverse effects like gastrointestinal
complications, retinopathy and QT interval prolongation are evident in treated
COVID-19 patients. But there is a lack of quality evidence to demonstrate CQ
and HCQ are effective in the treatment of COVID-19.
(4)The viral 3-chymotrypsin-like cysteine protease (3CLpro), playing pivotal
roles in coronavirus replication and polyprotein processing, is essential for its
life cycle. Therefore, inhibiting 3CLpro enzyme is also an important way to
block viral replication. The HIV inhibitor ritonavir/lopinavir can inhibit the
3CLpro enzyme action of COVID-19, and the oral
drug PF-07321332 developed by Pfizer has a similar mechanism. The addition
of ritonavir reduces the rate of metabolism of PF-07321332 by human cells
and enhances therapeutic concentrations.
(5)RNA-dependent RNA polymerase (RdRp) can synthesize new viral RNA
using viral single-stranded RNA as a template, therefore, viral replication can
also be blocked by inhibiting the action of RdRp. Remdesivir is a
phosphoramidate prodrug that is metabolized in cells to yield an active NTP
analog21 that we refer to as remdesivir triphosphate (RTP). RdRp can be
inserted into the RNA strand being extended using RTP as a substrate, after
which the replication process of RdRp is blocked. The nucleoside analogue
Remdesivir can avoid proofreading correction during RNA replication because
its incorporation does not immediately terminate the extension, but will block
RdRp only after the addition of three nucleotides [5].
(6) The oral drug Molnupiravir, developed by Merck as a substrate alternative
to cytidine/uridine triphosphate , can incorporates either A or G when RdRp
uses viral RNA as a template for replication, resulting in a mutated
RNA. Structural analysis of RdRp-RNA complexes containing mutated
products showed that Molnupiravir could form stable base pairs with either G
or A in the RdRp active center, which explains how the polymerase could
escape proofreading and synthesize mutated RNA. Unlike Remdesivir,
Molnupiravir does not block the action of RdRp, but reduces COVID-19 activity
by producing mutant viral RNA by a mechanism similar to that of Favipiravir
[6].

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Paxlovid and Molnupiravir: Difference In Mechanism of Action
In principle, Pfizer's oral drug PAXLOVID directly inhibits the action of
COVID-19 RNA polymerase, blocking the process of viral replication; while
Mercer's oral drug Molnupiravir does not block the replication of RNA, but
generates mutated genetic material by replacing C and G bases with fake
nucleoside analogues. However, it is still worth investigating whether the
mutated RNA is still virulent.
Conclusion
Vaccines, Remdesivir, Molnupiravir and PAXLOVID, despite their different
mechanisms of development, are all based on a deep understanding of viral
structure and physiological processes, and are effective weapons in our
response to COVID-19. Different R&D strategies may lead to different results.
As of now, Pfizer's oral drug works better than Merck Sharp & Dohme's, or
even other drugs, while Camostat Mesylate has been proven to be ineffective
in COVID-19 patients, but none of this can deny the exploration and efforts
made by the scientists behind it.
Huateng Pharma can offer pharmaceutical intermediate contract
manufacturing services. With comprehensive technical expertise and current
GMP facilities in China, we can provide custom synthesis for R&D and
commercial scaleup of these Paxlovid intermediates.
▶ CAS NO.67911-21-1 | Caronic anhydride
▶ CAS NO.194421-56-2 | 6,6-Dimethyl-3-Azabicyclo[3.1.0]hexane-2,4-dione
▶ CAS NO.565456-77-1 | (1R,2S,5S)-Methyl
6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride
▶ CAS NO.943516-54-9 | 6,6-Dimethyl-3-azabicyclo[3.1.0]hexane
References:
[1] Molnupiravir: What is the COVID-19 pill and how does it
work?, https://www.sciencefocus.com/news/molnupiravir-covid-pill/
[2] Pfizer’s Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk
of Hospitalization or Death by 89% in Interim Analysis of Phase 2/3 EPIC-HR
Study, https://www.pfizer.com/news/press-release/press-release-detail/pfizers
-novel-covid-19-oral-antiviral-treatment-candidate
[3] Boopathi S, Poma AB, Kolandaivel P. Novel 2019 coronavirus structure,
mechanism of action, antiviral drug promises and rule out against its
treatment. J Biomol Struct Dyn. 2021;39(9):3409-3418.
doi:10.1080/07391102.2020.1758788

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[4] Gunst, J. D., Staerke, N. B., Pahus, M. H., Kristensen, L. H., Bodilsen, J.,
Lohse, N., et al. (2021). Efficacy of the TMPRSS2 Inhibitor Camostat Mesilate
in Patients Hospitalized with Covid-19-A Double-Blind Randomized Controlled
Trial. EClinicalMedicine 35, 100849. doi:10.1016/j.eclinm.2021.100849
[5] Kokic, G., Hillen, H.S., Tegunov, D. et al. Mechanism of SARS-CoV-2
polymerase stalling by remdesivir. Nat Commun 12, 279
(2021). https://doi.org/10.1038/s41467-020-20542-0
[6] Kabinger, F., Stiller, C., Schmitzová, J. et al. Mechanism of
molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol
Biol 28, 740–746 (2021). https://doi.org/10.1038/s41594-021-00651-0
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