Correspondence:
Suvro Chatterjee Ph.D,
AU-KBC Research Centre,
MIT Campus of Anna University,
Chromepet, Chennai-600044, India.
Tel.: +91 44 2223 4885×48/+91 44 2223 2711×48;
Fax: +91 44 2223 1034
E-mail address:
soovro@yahoo.ca
Word count : 2,733
Acknowledgement : This project was partially supported by a
grant from University Grant Commission-Faculty Recharge Programme
(UGC-FRP), Government of India to SC.
Conflict of Interest : The authors declare that there are none.
Abstract
Background and Purpose : SARS-coV-2 pandemic continues to cause
an unprecedented global destabilization. There is an urgent need to
develop vaccines or identify molecules to treat severe cases and
repurposing of drugs is the best approach at this hour. Thalidomide,
despite having an infamous history has been successfully repurposed and
tested for various disease conditions including inflammatory diseases
and tumor. Few reports emphasize the use of thalidomide with a
SARS-coV-2 pneumonia patient being successfully treated with
thalidomide.
Experimental Approach: A meta-analysis comparing the
transcriptomes of SARS-coV-2 infected tissues with thalidomide and
lenalidomide-induced transcriptomic changes in transformed lung,
endothelial and hematopoietic models was performed.
Key Results: Thalidomide and lenalidomide exhibited pleiotropic
effects affecting a range of biological processes including
inflammation, immune response, angiogenesis, MAPK signaling, NOD-like
receptor signaling, TLR signaling, leukocyte differentiation and innate
immunity, the processes which are aberrantly regulated in severe
COVID-19 patients. In addition, we show the similarities between the
expression profiles of SARS-coV-2 infected lung and systemic lupus
erythematous.
Conclusion and Implications: The present study recommends
thalidomide analogs as a “better fit” to treat severe cases of novel
viral infections, healing the damaged network by compensating the
impairment caused by the Coronavirus disease-2019 (COVID-19).
Keywords: SARS-coV-2, Thalidomide, Lenalidomide, CC-220,
Pomalidomide, Inflammation, Immune Response, Angiogenesis
Abbreviations : COVID-19 - Coronavirus Disease -19; BALF –
Broncho-alveolar lavage fluid; PBMC – Peripheral Blood Mononuclear
Cell; DEG- Differentially Expressed Genes; GSEA – Gene Set Enrichment
Analysis; SLE – Systemic Lupus Erythematosus; TLR – Toll-like
Receptor; HUVEC – Human Umbilical Vein Endothelial Cell
Introduction
Novel coronavirus, SARS-coV-2 has been posing devastating effects on a
global scale with a soaring number of infections and an alarming rate of
mortality. Despite tremendous efforts, development of effective vaccines
or anti-viral medications is months away leaving repurposing of drugs
with known safety and efficacy profiles as the only viable choice.
COVID-19 is clinically very challenging since the novel coronavirus
triggers multi-organ turbulence devastating the homeostasis of the human
system. Once the SARS-CoV-2 virus enters the respiratory tract, there
are four different stages of the infection from symptoms to multi-organ
failures. Phase I starts with
the
ACE2 receptor-mediated viral entry through nasal and oral routes
followed by
host
immune system alert simultaneously with active viral replication in the
upper respiratory tract (Phase II). Next, Phase III coincides with minor
cytokine storm in the alveoli releasing the inflammatory cytokines
making the blood vessels leaky around the air sac, and ultimately the
second cytokine storm arrives with uncontrolled inflammatory and
life-threatening symptoms, acute respiratory distress syndrome (ARDS),
seizure, severe hypoxia and severed organ toxicity (Phase IV) .
Manifestation of the bi-phasic cytokine storm occurs through the
activation of a series of cytokines including granulocyte-colony
stimulating factor (G-CSF), interferon gamma-induced protein 10
(CXCL10), monocyte chemoattractant protein 1 (MCP1), macrophage
inflammatory protein 1α (MIP-1α), tumour necrosis factor α (TNF-α),
interleukin (IL)-2R and IL-6 overwhelming the system leading to
indiscriminate damages in multiple organs . There is an increased amount
of blood vessel growth in the lungs of COVID-19 patients compared to
severe influenza . Due to such multi-layers of problems associated with
the COVID-19 infections, researchers around the world are desperately in
search for a drug, which would able to tackle all or few of these
COVID-19 hallmarks.
Thalidomide, a small molecule drug, was marketed with an intention to
relieve morning sickness in pregnant women, and took a wrong turn that
resulted in children with birth defects upon in-utero exposure . Later,
thalidomide became a game changer for its the multi-faced
pharmacological effects such as immunomodulation, anti-inflammation,
anti-angiogenesis, and anti-viral effects . At this point of time, the
world needs a “smart” solution. Therefore, thalidomide raises the hope
for treating COVID-19 patients Chen et al reports successful treatment
of SARS-coV-2 associated pneumonia with combinatory treatment of
thalidomide and a low-dose glucocorticoid Two clinical trials,
NCT04273581 and NCT04273529 have been registered to check the efficacy
of thalidomide in treating COVID-19 patients. The adverse effects of
thalidomide and its analogs are well documented. Various genes
aberrantly expressed in SARS-coV-2 affected lungs are known targets of
thalidomide (Table S1). Extensive information available on thalidomide’s
mechanisms, their efficacy and safety in hemophagocytic syndrome-induced
cytokine storm and idiopathic pulmonary fibrosis , severe H1N1 and
paraquat poisoning lung injury argue for the possible action of
thalidomide on COVID-19 induced lung effects and cytokine storm.
Transcriptome-based approach to connect diseases with drug responses is
a recognized strategy in drug repurposing . With the fast-growing
literature on SARS-coV-2 infections, we performed meta-analysis of whole
transcriptome signatures of lungs, PBMC, BALF from SARS-coV-2 affected
patients and A549 cells and compared with the gene expression signatures
of thalidomide or lenalidomide-treated A549 (transformed adenocarcinoma
cells), hematopoietic and endothelial cells. We hereby provide possible
mechanistic actions of thalidomide in treating the SARS-coV-2 pathology.
In addition, we suggest that the derivatives of thalidomide,
lenalidomide and CC-220 might also be effective in the treatment of
SARS-coV-2.
Methods