Utility and feasibility of Phosphodiesterase inhibitors in the treatment COVID-19 patients
Introduction
The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the
subsequent COVID-19 pandemic have indeed presented a global health crisis of
unprecedented magnitude. The rapid spread of the virus, along with the severe health and
economic impacts it has had on communities around the world, underscores the urgent need
for effective treatments and management of the disease [13-16]. One of the most promising
approaches to managing the COVID-19 pandemic has been the development and distribution
of vaccines. Multiple vaccines have been developed and authorized for emergency use,
offering hope for controlling the spread of the virus and reducing the severity of illness [17-
21].
Treatment Development: While effective cures for COVID-19 have not yet been found,
researchers and pharmaceutical companies have been working to develop treatments that can
alleviate symptoms, reduce the severity of complications, and improve patient outcomes.
Various antiviral drugs and therapies have been explored for this purpose.
Antiviral Medications: Several antiviral medications, such as remdesivir, have received
Emergency Use Authorization for treating COVID-19. These drugs aim to inhibit the
replication of the virus within the body and may help to reduce the severity and duration of
illness.
Monoclonal Antibodies: Monoclonal antibody treatments have been developed and
authorized for emergency use. These treatments involve the infusion of lab-created antibodies
that can neutralize the virus and potentially reduce the severity of the disease, especially in
high-risk patients.
Research and Clinical Trials: Ongoing research and clinical trials are essential in the search
for effective treatments. Scientists and medical professionals continue to explore a range of
therapeutic options, including existing drugs that may have potential benefits against
COVID-19.
Public Health Measures: In addition to treatments, public health measures such as mask-
wearing, social distancing, testing, contact tracing, and quarantine efforts are vital for
controlling the spread of the virus and reducing its impact.
Vaccination Campaigns: Worldwide vaccination campaigns are crucial for achieving herd
immunity and ending the pandemic. Ensuring equitable access to vaccines for all countries
and populations is a significant challenge.
Healthcare System Strengthening: The pandemic has highlighted the importance of
strengthening healthcare systems to handle surges in cases. Adequate resources,
infrastructure, and a healthcare workforce are essential components in managing the
pandemic.
Variants and Adaptation: The emergence of new variants of the virus underscores the need
for ongoing vigilance and adaptability in public health and treatment strategies. Continued
surveillance and monitoring are essential.
International Collaboration: Global cooperation is critical in responding to a pandemic.
Sharing information, resources, and best practices is essential for an effective response [23-
29].
Seven known coronaviruses are reported to infect humans i.e. MERS-CoV, SARS-CoV,
HKU1, OC43, 229E, NL63, and the latest SARS-CoV-2 has brought the world on its feet [1].
Till now SARS-COV2 (COVID- 19 an RNA virus) has infected lakhs around the globe has
killed thousands and is moving the human race toward possible extinction. Research
scientists all over the world are looking for a drug or Vaccine that will save humans from this
dangerous Pandemic disease. Human Coronavirus encoded 2-5 OC43 ns2 /HEC4408 ns2
phosphodiesterases help these viruses to escape the host immunity [2,3]. In search of new
drugs, our group is trying to address the possibility of using FDA-approved
phosphodiesterase inhibitors or their structural analog for the treatment of COVID-19
infection. Currently, various Phosphodiesterase inhibitors have been approved by FDA.PDE4
inhibitors apremilast, roflumilast, and Crisbarole are the FDA-approved [4,5] drugs, used
respectively for the treatment of psoriatic arthritis, COPD, and atopic dermatitis [4,5].
Moreover, PDE4 inhibitor Roflumilast has been shown to inhibit respiratory s syncytial viral
infection in human differentiated bronchial epithelial cells [6]. Also, Type 4
phosphodiesterase inhibitors have been shown to attenuate viral-induced respiratory
inflammation FDA approved PDE5 inhibitors sildenafil, tadalafi, vardenafil, avanafil,
udenafil are primarily used for the treatment of erectile dysfunction [4,5]. About 30% of PDE
inhibitors in clinical development are PDE4 and PDE5 inhibitors [PDE Inhibitors Market,
2026 (DUBLIN, November 3, 2016 /PRNewswire)]. About 36% of the PDE inhibitors are
under development for the treatment of neurological disorders like Alzheimer’s,
Schizophrenia, and Huntington’s disease (DUBLIN, November 3, 2016 /PR News wire.
Various PDE5 inhibitors and Pan PDE inhibitors have been shown to induce neuro
differentiation in IMR32 neuroblastoma cells [7,8,9, 10, 11]. Structural analogs of sildenafil
have been shown to induce death of plasmodium species by inhibition of plasmodial-
phosphodiesterases [12]. Humans produce IFN gamma in response to viral infections. In
response to coronoviral infection, Interferon gamma-induces 2’-5’ oligoadenylate (2-5A)
synthetases (OASs) and ribonuclease (RNase) L are the main components host antiviral
pathway. Human and murine coronavirus produce ns2 phosphodiesterase that helps the virus
to survive by degradation of 2’-5’oligoadenylate (2-5A) [2,3]. ns2 coronoviral
phosphodiesterases are the important targets of phosphosphodiesterase inhibitors [2]. Since
currently available phosphodiesterase inhibitors are nonspecific and inhibit many
phosphodiesterase family members in humans and may target the coronavirus ns2
phosphodiesterases also (Fig1).
Corona virus
dsRNA
+3ATP
Host 2’-5’-oligoadenylate
(2-5A) synthetase
+
Interferon-γ
Host cell
2PPi+
2’-5’
oligoadenylate
RnaseL dimer
Degradation of viral RNA
Elimination of
Corona virus
Viral ns2 2’-5’ PDE
ATP+2AMP
NodegradationofdsRNA
leadingtoviralescapeand
furtherinfection
PDEinhbitor(Sildenafil,Roflumilast,Structuralanalog
ofSildenafil,Tadalafilroflumilastorspecificns2PDE
inhibitoretc
Synthesis of host enzymes
in nucleus in response to
IFN-γ
Fig 1. Mechanism of host immune evasion by Coronaviruses with the help of viral nS2
phosphodiesterase’s
Currently, available phosphodiesterase’s inhibitors are safer for use in humans and can be
tried in coronavirus patients. Since phosphodiesterase inhibitors increase the cellular cAMP
and cGMP levels which may be lethal to the survival of coronavirus in host cells [2,3] (Fig
2).
CellularcAMP,
cGMP in Alveolar
cells
Host PDEs
(PDE1-11)
5’ AMP, 5’ GMP Escape of Virus
Cellular cAMP, cGMP
Host PDEs
(PDE1-11)
5’AMP, 5’GMP
HighcellularcAMP
andcGMPislethal
tovirus
CocktailofPDEinhibitors
SildenafilandRoflumilast
oranyothersafePDE
inhibitorapprovedbyFDA
Viral infected Host cell
Fig 2. Role of Currently available FDA approved Phosphodiesterase inhibitors in eradication
of Virus
The combinatorial approach of FDA-approved phosphodiesterase inhibitors can be used in
optimal doses to prevent the viral escape and its pathogenesis. Moreover, structural analogs
of of FDA approved phosphodiesterase inhibitors can be synthesized which will specifically
target the viral ns2 phosphodiesterases leading to the elimination of the virus. Since PDE4
inhibitor roflumilast is an FDA-approved PDE4 inhibitor used for chronic obstructive
pulmonary disorder it can also be used in a patient infected with coronavirus because they
also have respiratory complications moreover it may also increase the cellular cAMP levels
in bronchial cells and may lead to degradation of corona viral RNA. Furthermore,
phosphodiesterase inhibitors can be also used in combination with the already approved
antivirals, In conclusion, a cocktail of PDE, Viral Protease, and reverse transcriptase
inhibitors could be a possible treatment for corona viral infection (Fig 3).
Viral infected Host cell
Nucleus
Elimination of virus from Host cell
Nucleus
DrugcocktailPDE,Viral
proteaseandreverse
transcriptaseinhibitors
Fig 3. Combinatorial Approach Viral protease inhibitors, reverse transcriptase inhibitors, and
Phosphodiesterase inhibitors for the treatment and elimination of viruses.
Conclusion
The COVID-19 pandemic has posed a significant challenge to the global community. While
the search for effective treatments continues, vaccination campaigns, public health measures,
and international collaboration remain key elements in controlling the spread of the virus and
mitigating its impact on public health and the economy. The urgency to address this ongoing
crisis remains high, and ongoing research and development are essential in the quest for more
effective treatments and long-term solutions. the utility and feasibility of Phosphodiesterase
inhibitors (PDE inhibitors) in the treatment of COVID-19 patients are subjects of ongoing
research and clinical evaluation. While there is a theoretical basis for considering PDE
inhibitors in COVID-19 treatment due to their anti-inflammatory, vasodilatory, and potential
antiviral properties, Current research on PDE inhibitors for COVID-19 is in the early stages,
with limited clinical data. Robust, well-designed clinical trials are needed to establish the
safety and efficacy of these drugs in the context of COVID-19. COVID-19 is a complex
disease with diverse clinical presentations, and patient outcomes can vary significantly. The
feasibility and effectiveness of PDE inhibitors may depend on factors such as the stage of the
disease and the patient’s overall health. In the absence of conclusive clinical evidence,
decisions about the utility and feasibility of PDE inhibitors in the treatment of COVID-19
patients should be made on a case-by-case basis, with careful consideration of the latest
research findings and in consultation with healthcare professionals. The ongoing research and
clinical trials will provide further insights into the role of PDE inhibitors in the management
of COVID-19. It’s important to stay updated on the latest developments and
recommendations from public health authorities and regulatory agencies.
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