Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 gene as a potential target for COVID-19 therapy

Zarubin, A. A.; Степанов, В. Г.; Марков, А. В.; Kolesnikov, N. A.; Марусин, А. В.; Khitrinskaya, I. Yu.; Swarovskaya, M. G.; Litvinov, Sergey; Ekomasova, Natalia; Dzhaubermezov, Murat; Maksimova, N.R.; Syromyatnikova, A. S.; Штыгашева, О. В.; Khusnutdinova, Elza; Radjabov, Magomed; Kharkov, V. N.

doi:10.1101/2020.06.20.156224

Cited by 7 publications

(3 citation statements)

References 38 publications

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“…In addition, the authors extrapolated nine drugs from the DRUGBANK database that could reduce the expression levels of TMPRSS2 . In particular, two of these drugs (Paracetamol and Curcumin) are currently being administered to alleviate some symptoms in COVID-19 patients [ 25 ]. In a study in vitro using cell lines and primary pulmonary cells, an inhibitor of the protease activity of TMPRSS2, camostat mesylate, partially inhibited the entry of SARS-CoV-2 into these lung epithelial cells [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

COVID-19 and Genetic Variants of Protein Involved in the SARS-CoV-2 Entry into the Host Cells

Latini

Agolini

Novelli

et al. 2020

Genes

103

106

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The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of TMPRSS2, PCSK3, DPP4, and BSG genes. In total we identified seventeen variants. In PCSK3 gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In TMPRSS2 gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity.

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Section: Discussionmentioning

confidence: 99%

COVID-19 and Genetic Variants of Protein Involved in the SARS-CoV-2 Entry into the Host Cells

Latini

Agolini

Novelli

et al. 2020

Genes

103

106

View full text Add to dashboard Cite

show abstract

“…The antiviral activities of Glycyrrhizin have been extensively studied in the context of other human viruses and most notably, the drug was found to potently suppress replication of two clinical isolates of SARS-associated coronavirus in Vero cells (49), and preliminarily, neutralize SARS-CoV-2 by inhibiting the viral main protease (50). Further, Carvedilol and Acetaminophen have been reported to decrease the expression of ACE2 and serine protease TMPRSS2, respectively (51,52), both of which are required for SARS-CoV-2 entry into cells (53). Hence, drug combinations that simultaneously exert both anti-inflammatory and antiviral effects against SARS-CoV-2 may have the greatest potential to be effective in treating COVID-…”

Section: Discussionmentioning

confidence: 99%

In vitroTargeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

Santoso

Rottenberg

et al. 2020

Preprint

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Treatment of the cytokine release syndrome (CRS) has become an important part of rescuing hospitalized COVID-19 patients. Here, we systematically explored the transcriptional regulators of inflammatory cytokines involved in the COVID-19 CRS to identify candidate transcription factors (TFs) for therapeutic targeting using approved drugs. We integrated a resource of TF-cytokine gene interactions with single-cell RNA-seq expression data from bronchoalveolar lavage fluid cells of COVID-19 patients. We found 581 significantly correlated interactions, between 95 TFs and 16 cytokines upregulated in the COVID-19 patients, that may contribute to pathogenesis of the disease. Among these, we identified 19 TFs that are targets of FDA approved drugs. We investigated the potential therapeutic effect of 10 drugs and 25 drug combinations on inflammatory cytokine production in peripheral blood mononuclear cells, which revealed two drugs that inhibited cytokine production and numerous combinations that show synergistic efficacy in downregulating cytokine production. Further studies of these candidate repurposable drugs could lead to a therapeutic regimen to treat the CRS in COVID-19 patients.

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“…By these reasons, it is important to predict the cancer patients’ susceptibility to SARS‐CoV‐2 infection and the disease outcome via assessing TMPRSS2 expression in cancer tissues, particular in prostate cancer tissues and related bioinformatics analyses. Thus, in this study, we performed the expression profile analyses of the TMPRSS2 gene for COVID‐19 in different normal tissues and PRAD (prostate adenocarcinoma) tumour tissues as a marker for targeted therapy 19‐21 …”

Section: Introductionmentioning

confidence: 99%

Prostate adenocarcinoma and COVID‐19: The possible impacts of TMPRSS2 expressions in susceptibility to SARS‐CoV‐2

Cheng

Zhou

et al. 2021

J Cellular Molecular Medi

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TMPRSS2 (OMIM: 602060) is a cellular protease involved in many physiological and pathological processes, and it facilitates entry of viruses such as SARS‐CoV‐2 into host cells. It is important to predict the prostate's susceptibility to SARS‐CoV‐2 infection in cancer patients and the disease outcome by assessing TMPRSS2 expression in cancer tissues. In this study, we conducted the expression profiles of the TMPRSS2 gene for COVID‐19 in different normal tissues and PRAD (prostate adenocarcinoma) tumour tissues. TMPRSS2 is highly expressed in normal tissues including the small intestine, prostate, pancreas, salivary gland, colon, stomach, seminal vesicle and lung, and is increased in PRAD tissues, indicating that SARS‐CoV‐2 might attack not only the lungs and other normal organs, but also in PRAD cancer tissues. Hypomethylation of TMPRSS2 promoter may not be the mechanism for TMPRSS2 overexpression in PRAD tissues and PRAD pathogenesis. TMPRSS2 expresses eleven isoforms in PRAD tissues, with the TMPRSS2‐001 isoform expressed highest and followed by TMPRSS2‐201. Further isoform structures prediction showed that these two highly expressed isoforms have both SRCR_2 and Trypsin (Tryp_SPc) domains, which may be essential for TMPRSS2 functional roles for tumorigenesis and entry for SARS‐CoV‐2 in PRAD patients. Analyses of functional annotation and enrichment in TMPRSS2 showed that TMPRSS2 is mostly enriched in regulation of viral entry into host cells, protein processing and serine‐type peptidase activity. TMPRSS2 is also associated with prostate gland cancer cell expression, different complex(es) formation, human influenza and carcinoma, pathways in prostate cancer, influenza A, and transcriptional misregulation in cancer. Altogether, even though high expression of TMPRSS2 may not be favourable for PRAD patient's survival, increased expression in these patients should play roles in susceptibility of the SARS‐CoV‐2 infection and clinical severity for COVID‐19, highlighting the value of protective actions of PRAD cases by targeting or androgen‐mediated therapeutic strategies in the COVID‐19 pandemic.

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Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 gene as a potential target for COVID-19 therapy

Cited by 7 publications

References 38 publications

COVID-19 and Genetic Variants of Protein Involved in the SARS-CoV-2 Entry into the Host Cells

COVID-19 and Genetic Variants of Protein Involved in the SARS-CoV-2 Entry into the Host Cells

In vitroTargeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

Prostate adenocarcinoma and COVID‐19: The possible impacts of TMPRSS2 expressions in susceptibility to SARS‐CoV‐2

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