Ubiquitin-dependent proteolysis, a therapeutic strategy: An interface between health and disease

All eukaryotic cells have a system in place called the ubiquitin-dependent proteolysis system to control protein degradation;nevertheless, any flaws in this system can initiate numerous fatal diseases, including cancer, metabolic problems, neurological disorders and diseases. These health complications interlink with faults in ubiquitin-dependent proteolysis. Ubiquitin assists as a post-translational targeting signal for altering the structure, localization of other proteins, features and functioning styles of the cells and tissues. The ubiquitin ligase standardizes the specific nature of the ubiquitination features and cellular response. The ubiquitin ligase is a critical element of the enzymatic cascade that regulates the part of the multipubiquitin chain to the target or labile protein. Consequently, the attachment of the ubiquitin topology is crucial for regulating healthy growth, differentiation, and protection of cells from damage by xenobiotics, infections, mutations, and environmental stresses. Protein degradation is adopted by the cells as a route to enduringly deactivate proteins. The 26S proteasome is responsible for ATP-dependent protein failure in the cytoplasm and nuclei of eukaryotes. Most proteins are covalently associated with a multi-ubiquitin chain and engage the 26S proteasome. In the testes, the ubiquitin ligases E1, E2, E3, and UBC4 are dynamic. Here, prompt and large protein alterations are essential for a cell to respond to its environment, and a complex web of interrelated events, including control over synthesis, localization, and degradation. The regulator of the cell cycle, receptor processing, growth management, and stress response are all subject to intracellular proteolysis. This chapter focuses on (I) the significant contribution of ubiquitination in the cellular signaling pathways that contract with these external influences;(II) the mechanisms of ubiquitination-deubiquitination that offer the system its high level of selectivity, (III) the role of ubiquitin-dependent degradation in initiating diseases in humans and forthcoming clinical claims developed to employ the cell's built-in proteolytic machinery to cure diseases;(IV) to examine imaginable clinical practices fashioned to exploit the body's own proteolytic machinery to cure the diseases, and analyze the effectiveness of vaccinations, antibodies, and other possible therapies that aim to block SARS-CoV-2 entrance pathways. Lastly, the authors include the most important unanswered queries pertaining to this crucial route. © 2023 Nova Science Publishers, Inc.

Recent Advances in PROTAC-Based Antiviral Strategies.

Numerous mysteries of cell and molecular biology have been resolved through extensive research into intracellular processes, which has also resulted in the development of innovative technologies for the treatment of infectious and non-infectious diseases. Some of the deadliest diseases, accounting for a staggering number of deaths, have been caused by viruses. Conventional antiviral therapies have been unable to achieve a feat in combating viral infections. As a result, the healthcare system has come under tremendous pressure globally. Therefore, there is an urgent need to discover and develop newer therapeutic approaches against viruses. One such innovative approach that has recently garnered attention in the research world and can be exploited for developing antiviral therapeutic strategies is the PROteolysis TArgeting Chimeras (PROTAC) technology, in which heterobifunctional compounds are employed for the selective degradation of target proteins by the intracellular protein degradation machinery. This review covers the most recent advancements in PROTAC technology, its diversity and mode of action, and how it can be applied to open up new possibilities for creating cutting-edge antiviral treatments and vaccines.

AMICOUMACIN-BASED PRODRUG DEVELOPMENT APPROACH

Coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, is highly contagious and has a severe morbidity. Providing care to patients with COVID-19 requires the development of new types of antiviral drugs. The aim of this work is to develop a prodrug for the treatment of coronavirus disease using the antibiotic Amicoumacin A (Ami), the mechanism of action of which is based on translation inhibition. Enzymatic hydrolysis of an inactivated prodrug by the SARS-CoV-2 main protease can lead to the release of the active Ami molecule and, as a consequence, the suppression of protein biosynthesis in infected cells. To test the proposed hypothesis, a five-stage synthesis of an inactivated analogue of Amicoumacin A was carried out. Its in vitro testing with the SARS-CoV-2 recombinant protease MPro showed a low percentage of hydrolysis. Further optimization of the peptide fragment of the inactivated analog recognized by the SARS-CoV-2 MPro protease may lead to an increase in proteolysis and the release of Amicoumacin A.

Steroids - Exploitation

Corticosteroids, more specifically glucocorticoids are one of the most prescribed drugs. Corticosteroids are adrenal hormones that serve significant physiologic activities such as modulating glucose metabolism, protein catabolism, calcium metabolism, bone turnover control, immunosuppression, and down-regulation of inflammatory cascade. Corticosteroids are regarded life-saving due to their various effects and have been used therapeutically to treat broad range of auto-immune, rheumatologic, inflammatory, neoplastic, and viral illnesses.However, the therapeutic benefits of glucocorticoids are restricted by the adverse effects. The most serious side effects of corticosteroids are associated with the use of higher doses for longer periods and OTC availability in specific pharmacies, which leads to dependency, as well as its usage in mild and moderate server instances, which is contrary to guidelines. In the recent times the use of corticosteroids has been multiplied with the emergence of the Covid -19 pandemic. WHO and the standard guidelines has recommended the usage of corticosteroids in critically ill covid-19 patients but their usage in mild and moderate cases caused more harm than benefit. This illicit usage has resulted in the development of opportunistic fungal illnesses such as mucormycosis, posing an extra risk to patients in terms of quality of life and finances. Other adverse effects of systemic corticosteroids include morphological changes, increased blood sugar levels, delayed wound healing, infections, decreased bone density, truncal obesity, cataracts, glaucoma, blood pressure abnormalities, and muscle fibre atrophy.In this review we want to discuss the significance and detrimental effects of corticosteroids emphasizing on the recent times i.e., COVID-19.

Circulating Peptidome Is Strongly Altered in COVID-19 Patients.

Whilst the impact of coronavirus disease 2019 (COVID-19) on the host proteome, metabolome, and lipidome has been largely investigated in different bio-fluids, to date, the circulating peptidome remains unexplored. Thus, the present study aimed to apply an untargeted peptidomic approach to provide insight into alterations of circulating peptides in the development and severity of SARS-CoV-2 infection. The circulating peptidome from COVID-19 severe and mildly symptomatic patients and negative controls was characterized using LC-MS/MS analysis for identification and quantification purposes. Database search and statistical analysis allowed a complete characterization of the plasma peptidome and the detection of the most significant modulated peptides that were impacted by the infection. Our results highlighted not only that peptide abundance inversely correlates with disease severity, but also the involvement of biomolecules belonging to inflammatory, immune-response, and coagulation proteins/processes. Moreover, our data suggested a possible involvement of changes in protein degradation patterns. In the present research, for the first time, the untargeted peptidomic approach enabled the identification of circulating peptides potentially playing a crucial role in the progression of COVID-19.

Trajectories of UCR as a measure of biological mechanisms underlying ethnicity associated outcomes in COVID-19

Introduction: Patients with Black and Asian ethnic background have been disproportionately affected by COVID-19 with increased disease severity, organ failure, intensive care admission, and premature mortality. 1-3 The urea-to-creatinine ratio (UCR) has been described as a biochemical signature of persistent critical illness, its hallmark catabolic state and late mortality during prolonged ICU stay.4 Low serum creatinine reflecting reduced muscle mass, which declines rapidly in acute severe illness in combination with net muscle protein breakdown which contribute substrate for increased hepatic urea synthesis, results in markedly elevated UCR. Objectives: To assess UCR as a candidate biological feature driving ethnicity associated outcomes of COVID-19 disease. Methods: Prospective analysis using registry data from all patients aged ≥16 years with an emergency admission to hospitals within Barts Health NHS Trust with SARSCoV-2 infection during 1 January 2020 - 13 May 2020 (wave 1), and 1 September 2020 -17 February 2021 (wave 2). Trajectories of routine haematology and clinical biochemistry blood results during hospital admission were assessed, and distinct phenotypes defined using unsupervised longitudinal clustering techniques using day 0 to 15 results.We determined distribution of identified phenotypes within patients categorised by ethnic group. Multivariable logistic regression accounting for predefined baseline risk factors was used to assess association between ethnicity, phenotypes, and 30-day mortality. All analyses were performed using R software v4.02 and the kml package for clustering. 5 Results are presented as n (%) and adjusted odds ratios (OR) with 95% confidence intervals. Results: We assessed 459 (wave 1) and 1337 (wave 2) patients after excluding those with unknown ethnicity and those with <7 blood results. Three clusters were identified based on trajectories of UCR. In wave 1, 48.1% of patients had persistently low levels of UCR (A), 38.6% had higher but stable levels (B), and 13.3% had the highest levels peaking after day 7 (C). In wave 2, three clusters were identified in similar proportions: 42.8% (a), 45.1% (b), 12.1% (c). In wave 1, patients in cluster C compared to A had the highest risk of death at 30 days (OR 4.59 [2.27-9.26], p<0.001). In wave 2, both clusters b (OR 1.58 [1.18-2.12], p< 0.001) and c (OR 3.96 [2.62-5.99], p<0.001) had higher risk of death compared to a. Distribution of cluster membership varied by ethnic category. In both waves, greater proportions of patients within cluster A/a were observed in patients with Black ethnicity (65.5% wave 1, 61.1% wave 2) compared to Asian (50.0% wave 1, 37.3% wave 2) and White (39.7% wave 1, 39.6% wave 2) ethnicity. Black ethnicity patients also had lowest proportions in cluster C/c (6.9% wave 1, 6.3% wave 2) compared to Asian (17.4% wave 1, 14.2% wave 2) and White (13.2% wave 1, 12.9% wave 2) ethnicity. Inclusion of UCR trajectory attenuated the higher risk of death seen in Asian patients in wave 1. Conclusion: Phenotypes based on UCR trajectories during hospital admission are associated with adverse outcomes following COVID-19 infection. Further work is needed to understand phenotypes of prolonged COVID-19 disease muscle wasting and its association with longerterm outcomes.

Plasma and Airway Levels of Surfactant Protein D Degradation Reflect Progression of ARDS in Ventilated Patients with SARS-CoV-2

Background: Patients with COVID-19 present severe respiratory symptoms progressing to acute respiratory distress syndrome (ARDS). Upon infection, SARS-CoV-2 destroys cells expressing the ACE2 receptor including alveolar type II cells (AT2). These cells are found in the alveolar-capillary barrier which normally secrete pulmonary surfactant, a complex of lipid and surfactant proteins (SPA, SP-B, SP-C, SP-D). Exogenous surfactant therapy (mainly composed of phospholipids, SP-B, and SP-C) has been successful in treating neonatal respiratory distress syndrome (nRDS) caused by surfactant deficiency in preterm babies.Plasma SP-D has been proposed as a marker of lung injury in COVID-19 but so far, no reports have evaluated sequential SP-D levels in both airway and plasma. As part of a clinical trial repurposing surfactant therapy to treat adult ventilated COVID-19 patients, we hypothesized that plasma SP-D levels may reflect decreased lung integrity and that SP-D degradation in plasma and airway samples from COVID-19 patients may reflect disease progression and severity. Methods: Enzyme-linked immunosorbent assay (ELISA) was used to quantify SP-D concentration in patient plasma and tracheal aspirate samples. Western Blotting was used to identify any protein degradation. Sequential daily plasma and airway samples were analysed. Results: SP-D concentration in serum was 10-20 times higher in patients ventilated for COVID-19 than in healthy volunteers. Additionally, the concentration of SP-D in plasma has shown to be 10-100-fold higher than in tracheal aspirates. Furthermore, degraded fragments of SP-D were detected at a higher ratio than intact SP-D in plasma of ventilated patients. This ratio decreased with administration of surfactant therapy (containing phospholipids and SP-B and SP-C but no SPA or SP-D). Conclusions: Increased serum SP-D and decreased tracheal aspirate SP-D from ventilated COVID-19 patients suggested leakage of pulmonary surfactant into the bloodstream caused by damage to the alveolar-capillary barrier in diseased lungs. The ratio of degraded vs. intact SP-D found in the plasma was compared before and after therapeutic surfactant administration. The results indicated that levels of SP-D in plasma and tracheal aspirates together with the ratio of degraded and intact SP-D in the plasma may be useful indicators of the severity of COVID-19 lung disease progression.

The Multifaceted Role of the Ubiquitin Proteasome System in Pathogenesis and Diseases.

Ubiquitin is a small protein that is conjugated to target proteins to signal a great number of critical biological processes. Impaired ubiquitin signaling and defects in the ubiquitin proteasome system (UPS) surveillance are implicated in many human diseases, including cancer. Characterization of the physiological roles of UPS components and their regulatory mechanisms is therefore vital for the identification of therapeutic targets and the development of tools and paradigms to better understand and treat human diseases. In this Special Issue, we assembled seven original research and review articles to provide insights on the multifaceted role of the UPS in pathogenesis and disease, covering the areas of molecular and cellular mechanisms of UPS enzymes, biochemical and biophysical characterization strategies, drug development, and targeted protein degradation.

Stability of SARS-CoV-2-Encoded Proteins and Their Antibody Levels Correlate with Interleukin 6 in COVID-19 Patients.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has become a severe global public health crisis. Therefore, understanding the molecular details of SARS-CoV-2 will be critical for fighting the virus's spread and preventing future pandemics. In this study, we globally profiled the stability of SARS-CoV-2-encoded proteins, studied their degradation pathways, and determined their correlation with the antibody responses in patient plasma. We identified 18 proteins with unstable half-lives and 6 relatively stable proteins with longer half-lives. The labile SARS-CoV-2 proteins were degraded mainly by the ubiquitin-proteasome pathway. We also observed a significant correlation between antibody levels and protein half-lives, which indicated that a stable antigen of SARS-CoV-2 could be more effective for eliciting antibody responses. In addition, levels of antiviral antibodies targeting NSP10 were found to be negatively correlated with systemic levels of interleukin 6 (IL-6) in patients. These findings may facilitate the development of novel therapeutic or diagnostic approaches. IMPORTANCE SARS-CoV-2, the etiological cause of COVID-19, carries 29 genes in its genome. However, our knowledge of the viral proteins in biological and biochemical aspects is limited. In this study, we globally profiled the stability of the viral proteins in living lung epithelial cells. Importantly, the labile SARS-CoV-2-encoded proteins were mainly degraded through the ubiquitin-proteasome pathway. Stable proteins, including spike and nucleocapsid, of SARS-CoV-2 were more effective in eliciting antibody production. The levels of antiviral antibodies targeting NSP10 were negatively correlated with systemic levels of IL-6 in COVID-19 patients.

Targeted protein degradation: from small molecules to complex organelles-a Keystone Symposia report.

Targeted protein degradation is critical for proper cellular function and development. Protein degradation pathways, such as the ubiquitin proteasomes system, autophagy, and endosome-lysosome pathway, must be tightly regulated to ensure proper elimination of misfolded and aggregated proteins and regulate changing protein levels during cellular differentiation, while ensuring that normal proteins remain unscathed. Protein degradation pathways have also garnered interest as a means to selectively eliminate target proteins that may be difficult to inhibit via other mechanisms. On June 7 and 8, 2021, several experts in protein degradation pathways met virtually for the Keystone eSymposium "Targeting protein degradation: from small molecules to complex organelles." The event brought together researchers working in different protein degradation pathways in an effort to begin to develop a holistic, integrated vision of protein degradation that incorporates all the major pathways to understand how changes in them can lead to disease pathology and, alternatively, how they can be leveraged for novel therapeutics.

Demonstration of virulence factors of Trichosporon species isolated from clinical samples during the COVID 19 pandemic - A study from a tertiary care medical college hospital from South India

Background:Genus Tricosporon consists of basidiomycetous yeast that form a part of the human microbiota.They cause an array of human diseases, both in imunocompetant and immunocompromised patients. They are the second most commonly reported cause of disseminated infections in humans. Their ability to form Biofilms make them a potential agent of Catheter associated Fungemia. They exhibit virulence factors like Biofilm formation, hemolysis and produce enzymes like proteases and phospholipases that increases the pathogenicity by breaking down the proteins and dis- rupting the host cell membranes. The proteolytic activity plays an important role in its pathogenicity by facilitating inva- sion through degradation of keratin and collagen. Methods:This observational period study was performed at our hospital from 20/06/2020 to 20/10/2020.The isolates were subjected to tests to demonstrate virulence factors. Determination of phospholipase activity was performed using using egg yolk agar, hemolytic activity by SDA with 7% sheep blood, esterase activity was determined by using Tween -80 opacity test medium and the production of Biofilm formation was done by micro titre plate method. All results were recorded. The isolates were confirmed by MALDI TOF mass spectrometry. Results:1.Colony morphology 2.Urease production using christensons urea agar (2%) 3.Phenotypic and Biochemical test result were per- formed and tabulated. Proteomic confirmation results are awaited. [Formula presented] Conclusions:Knowing the virulence factor and the commonly occurring Trichosporon species aids in understanding the pathogenesis and to plan strategic treatment modalities

Relapsed/Refractory Multiple Myeloma in 2020/2021 and Beyond.

Despite the challenges imposed by the COVID-19 pandemic, exciting therapeutic progress continues to be made in MM. New drug approvals for relapsed/refractory (RR)MM in 2020/2021 include the second CD38 monoclonal antibody, isatuximab, the first BCMA-targeting therapy and first-in-class antibody-drug conjugate (ADC) belantamab mafodotin, the first BCMA-targeting CAR T cell product Idecabtagen-Vicleucel (bb2121, Ide-Cel), the first in-class XPO-1 inhibitor selinexor, as well as the first-in-class anti-tumor peptide-drug conjugate, melflufen. The present introductory article of the Special Issue on "Advances in the Treatment of Relapsed and Refractory Multiple Myeloma: Novel Agents, Immunotherapies and Beyond" summarizes the most recent registration trials and emerging immunotherapies in RRMM, gives an overview on latest insights on MM genomics and on tumor-induced changes within the MM microenvironment, and presents some of the most promising rationally derived future therapeutic strategies.

[Induced degradation of proteins by PROTACs and other strategies: towards promising drugs]. / Dégradation induite des protéines par des molécules PROTAC et stratégies apparentées : développements à visée thérapeutique.

Targeted protein degradation (TPD), discovered twenty years ago through the PROTAC technology, is rapidly developing thanks to the implication of many scientists from industry and academia. PROTAC chimeras are heterobifunctional molecules able to link simultaneously a protein to be degraded and an E3 ubiquitin ligase. This allows the protein ubiquitination and its degradation by 26S proteasome. PROTACs have evolved from small peptide molecules to small non-peptide and orally available molecules. It was shown that PROTACs are capable to degrade proteins considered as "undruggable" i.e. devoid of well-defined pockets and deep grooves possibly occupied by small molecules. Among these "hard to drug" proteins, several can be degraded by PROTACs: scaffold proteins, BAF complex, transcription factors, Ras family proteins. Two PROTACs are clinically tested for breast (ARV471) and prostate (ARV110) cancers. The protein degradation by proteasome is also induced by other types of molecules: molecular glues, hydrophobic tagging (HyT), HaloPROTACs and homo-PROTACs. Other cellular constituents are eligible to induced degradation: RNA-PROTACs for RNA binding proteins and RIBOTACs for degradation of RNA itself (SARS-CoV-2 RNA). TPD has recently moved beyond the proteasome with LYTACs (lysosome targeting chimeras) and MADTACs (macroautophagy degradation targeting chimeras). Several techniques such as screening platforms together with mathematical modeling and computational design are now used to improve the discovery of new efficient PROTACs.

TITLE: Dégradation induite des protéines par des molécules PROTAC et stratégies apparentées : développements à visée thérapeutique. ABSTRACT: Alors que, pour la plupart, les médicaments actuels sont de petites molécules inhibant l'action d'une protéine en bloquant un site d'interaction, la dégradation ciblée des protéines, découverte il y a une vingtaine d'années via les petites molécules PROTAC, connaît aujourd'hui un très grand développement, aussi bien au niveau universitaire qu'industriel. Cette dégradation ciblée permet de contrôler la concentration intracellulaire d'une protéine spécifique comme peuvent le faire les techniques basées sur les acides nucléiques (oligonucléotides antisens, ARNsi, CRISPR-Cas9). Les molécules PROTAC sont des chimères hétéro-bifonctionnelles capables de lier simultanément une protéine spécifique devant être dégradée et une E3 ubiquitine ligase. Les PROTAC sont donc capables de provoquer l'ubiquitinylation de la protéine ciblée et sa dégradation par le protéasome 26S. De nature peptidique, puis non peptidique, les PROTAC sont maintenant administrables par voie orale. Ce détournement du système ubiquitine protéasome permet aux molécules PROTAC d'élargir considérablement le champ des applications thérapeutiques puisque l'élimination de protéines dépourvues de poches ou de crevasses bien définies, dites difficiles à cibler, devient possible. Cette technologie versatile a conduit à la dégradation d'une grande variété de protéines comme des facteurs de transcription, des sérine/thréonine/tyrosine kinases, des protéines de structure, des protéines cytosoliques, des lecteurs épigénétiques. Certaines ligases telles que VHL, MDM2, cereblon et IAP sont couramment utilisées pour être recrutées par les PROTAC. Actuellement, le nombre de ligases pouvant être utilisées ainsi que la nature des protéines dégradées sont en constante augmentation. Deux PROTAC sont en étude clinique pour les cancers du sein (ARV471) et de la prostate (ARV110). La dégradation spécifique d'une protéine par le protéasome peut aussi être induite par d'autres types de molécules synthétiques : colles moléculaires, marqueurs hydrophobes, HaloPROTAC, homo-PROTAC. D'autres constituants cellulaires sont aussi éligibles à une dégradation induite : ARN-PROTAC pour les protéines se liant à l'ARN et RIBOTAC pour la dégradation de l'ARN lui-même comme celui du SARS-CoV-2. Des dégradations induites en dehors du protéasome sont aussi connues : LYTAC, pour des chimères détournant la dégradation de protéines extracellulaires vers les lysosomes, et MADTAC, pour des chimères détournant la dégradation par macroautophagie. Plusieurs techniques, en particulier des plates-formes de criblage, la modélisation mathématique et la conception computationnelle sont utilisées pour le développement de nouveaux PROTAC efficaces.

Proteasome activator PA28γ-dependent degradation of coronavirus disease (COVID-19) nucleocapsid protein.

The nucleocapsid protein is significant in the formation of viral RNA of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), accounting for the largest proportion of viral structural proteins. Here, we report for the first time that the 11S proteasomal activator PA28γ regulates the intracellular abundance of the SARS-CoV-2 N protein (nCoV N). Furthermore, we have identified proteasome activator PA28γ as a nCoV N binding protein by co-immunoprecipitation assay. As a result of their interaction, nCoV N could be degraded by PA28γ-20S in vitro degradation assay. This was also demonstrated by blocking de novo protein synthesis with cycloheximide. The stability of nCoV N in PA28γ-knockout cells was greater than in PA28γ-wildtype cells. Notably, immunofluorescence staining revealed that knockout of the PA28γ gene in cells led to the transport of nCoV N from the nucleus to the cytoplasm. Overexpression of PA28γ enhanced proteolysis of nCoV N compared to that in PA28γ-N151Y cells containing a dominant-negative PA28γ mutation, which reduced this process. These results suggest that PA28γ binding is important in regulating 20S proteasome activity, which in turn regulates levels of the critical nCoV N nucleocapsid protein of SARS-CoV-2, furthering our understanding of the pathogenesis of COVID-19.

SUMO pathway, blood coagulation and oxidative stress in SARS-CoV-2 infection.

Severe Acute Respiratory Syndrome Corona Virus 2 (SARS CoV-2) is currently an international pandemic causing coronavirus disease 19 (COVID-19). Viral entry requires ACE2 and transmembrane protease serine 2 (TMPRSS2) for membrane fusion or through endosomal pathway. This Study aims to assess transcriptomic changes and differentially expressed genes (DFGs) in COVID-19. METHODS: Transcriptomic data of the publicly available dataset (GSE147507) was quantile normalized and analysed for DFGs, network analysis and pathway analysis. RESULTS: DFG sets showed that 8 genes (SAE1, AEBP2, ATP1A1, DKK3, MAFF, NUDC, TRAP1, and VAV1) were significantly dysregulated in all studied groups. Functional analysis revealed that negative regulation of glucocorticoid biosynthesis, protein SUMOylation (SAE1), blood coagulation (VAV1) and cellular response to stress were affected by SARS CoV-2 infection. Cell line transduction with ACE2 vector didn't show significant changes in the dysregulated pathways. Also, no significant change was observed in expression levels of ACE2 or TMPRSS2 in response to SARS CoV-2 infection. Further analysis showed dysregulation of several genes in the SUMOylation pathway and blood coagulation process in human and cell lines transcriptome. Also, several Cathepsins proteases were significantly dysregulated in case of SARS CoV-2 infection. Genes related to cellular response to stress such as TRAP-1 and NOX were dysregulated in cases of SARS CoV-2 infection. CONCLUSION: Dysregulation in genes of protein SUMOylation, blood coagulation and response to oxidative stress pathways in SARS CoV-2 infection could be critical for disease progression. Drugs acting on SUMO pathway, VAV1, NOX genes could be studied for potential benefit to COVID-19 patients.