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