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1.
Sovrem Tekhnologii Med ; 12(6): 98-108, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34796023

RESUMEN

The rapidly accumulating information about the new coronavirus infection and the ambiguous results obtained by various authors necessitate further research aiming at prevention and treatment of this disease. At the moment, there is convincing evidence that the pathogen affects not only the respiratory but also the central nervous system (CNS). The aim of the study is to provide an insight into the molecular mechanisms underlying the damage to the CNS caused by the new coronavirus SARS-CoV-2. Results: By analyzing the literature, we provide evidence that the brain is targeted by this virus. SARS-CoV-2 enters the body with the help of the target proteins: angiotensin-converting enzyme 2 (ACE2) and associated serine protease TMPRSS2 of the nasal epithelium. Brain damage develops before the onset of pulmonary symptoms. The virus spreads through the brain tissue into the piriform cortex, basal ganglia, midbrain, and hypothalamus. Later, the substantia nigra of the midbrain, amygdala, hippocampus, and cerebellum become affected. Massive death of neurons, astrogliosis and activation of microglia develop at the next stage of the disease. By day 4, an excessive production of proinflammatory cytokines in the brain, local neuroinflammation, breakdown of the blood-brain barrier, and impaired neuroplasticity are detected. These changes imply the involvement of a vascular component driven by excessive activity of matrix metalloproteinases, mediated by CD147. The main players in the pathogenesis of COVID-19 in the brain are products of angiotensin II (AT II) metabolism, largely angiotensin 1-7 (AT 1-7) and angiotensin IV (AT IV). There are conflicting data regarding their role in damage to the CNS in various diseases, including the coronavirus infection.The second participant in the pathogenesis of brain damage in COVID-19 is CD147 - the inducer of extracellular matrix metalloproteinases. This molecule is expressed on the endothelial cells of cerebral microvessels, as well as on leukocytes present in the brain during neuroinflammation. The CD147 molecule plays a significant role in maintaining the structural and functional integrity of the blood-brain barrier by controlling the basal membrane permeability and by mediating the astrocyte-endothelial interactions. Via the above mechanisms, an exposure to SARS-CoV-2 leads to direct damage to the neurovascular unit of the brain.


Asunto(s)
Astrocitos/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , SARS-CoV-2/metabolismo , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Angiotensina II/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Basigina , Humanos , Fragmentos de Péptidos/metabolismo , Serina Endopeptidasas/metabolismo
2.
J Biosci ; 462021.
Artículo en Inglés | MEDLINE | ID: mdl-34785628

RESUMEN

Since the start of the pandemic, SARS-CoV-2 has infected almost 200 million human hosts and is set to encounter and gain entry in many more in the coming months. As the coronavirus flourish, the evolutionary pressure selects those variants that can complete the infection cycle faster and reproduce in large numbers compared to others. This increase in infectivity and transmissibility coupled with the immune response from high viral load may cause moderate to severe disease. Whether this leads to enhanced virulence in the prevalent Alpha and Delta variants is still not clear. This review describes the different types of SARS-CoV-2 variants that are now prevalent, their emergence, the mutations responsible for their growth advantages, and how they affect vaccine efficacy and increase chances of reinfection. Finally, we have also summarized the efforts made to recognize and predict the mutations, which can cause immune escape and track their emergence through impactful genomic surveillance.


Asunto(s)
Anticuerpos Neutralizantes/química , COVID-19/epidemiología , Genoma Viral , Evasión Inmune/genética , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/química , Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/inmunología , Anticuerpos Neutralizantes/genética , Anticuerpos Neutralizantes/inmunología , Sitios de Unión , COVID-19/patología , COVID-19/transmisión , COVID-19/virología , Vacunas contra la COVID-19 , Humanos , Modelos Moleculares , Mutación , Filogenia , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores Virales/química , Receptores Virales/genética , Receptores Virales/inmunología , SARS-CoV-2/clasificación , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Virulencia
3.
Nanoscale ; 13(45): 19218-19237, 2021 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-34787160

RESUMEN

The global dissemination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has seriously endangered human health. The number of confirmed cases is still increasing; however, treatment options are limited. Transmembrane protease serine 2 (TMPRSS2), as a key protease that primes the binding of SARS-CoV-2 spike protein and angiotensin-converting enzyme 2 (ACE2), has become an attractive target and received widespread attention. Thus, four potential drugs (bromhexine, camostat, gabexate, and nafamostat) were used to explore the mechanism of binding with TMPRSS2 in this work. A 65 ns molecular dynamics simulation was performed three times for each drug-TMPRSS2 system for reliable energy calculation and conformational analysis, of which the simulations of nafamostat-TMPRSS2 systems were further extended to 150 ns three times due to the discovery of two binding modes. Through the results of calculating binding free energy by nine methods, the binding affinity of camostat, gabexate, and nafamostat to TMPRSS2 showed great advantages compared with bromhexine, where the nafamostat was surprisingly found to present two reasonable binding conformations (forward and reverse directions). Two negatively charged amino acids (Asp435 and Glu299) can clamp the two positively charged groups (guanidinium group and amidinium group) in either forward or reverse fashion, and the forward one is more stable than the reverse. In addition, compared with gabexate, the dimethylamino group in camostat forms more van der Waals interactions with surrounding hot-spots His296 and Val280, resulting in a stronger affinity to TMPRSS2. For bromhexine, multiple binding sites are displayed in the binding pocket due to its small molecular structure, and van der Waals interactions play the dominant role in the binding process. In particular, six typical hot-spots were identified in the last three serine protease inhibitor systems, i.e., Asp435, Ser436, Gln438, Trp461, Ser463, and Gly464. The guanidinium groups of the drugs have powerful interactions with adjacent residues due to the formation of more hydrogen bonds, suggesting that this may be the critical site for drug design against TMPRSS2. This work provides valuable molecular insight into these four drug-TMPRSS2 binding mechanisms and is helpful for designing and screening drugs targeting TMPRSS2.


Asunto(s)
COVID-19 , Preparaciones Farmacéuticas , Humanos , Simulación de Dinámica Molecular , SARS-CoV-2 , Serina Endopeptidasas/genética , Glicoproteína de la Espiga del Coronavirus
4.
Front Cell Infect Microbiol ; 11: 763152, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34790590

RESUMEN

The pathobiont Streptococcus pneumoniae causes life-threatening diseases, including pneumonia, sepsis, meningitis, or non-invasive infections such as otitis media. Serine proteases are enzymes that have been emerged during evolution as one of the most abundant and functionally diverse group of proteins in eukaryotic and prokaryotic organisms. S. pneumoniae expresses up to four extracellular serine proteases belonging to the category of trypsin-like or subtilisin-like family proteins: HtrA, SFP, PrtA, and CbpG. These serine proteases have recently received increasing attention because of their immunogenicity and pivotal role in the interaction with host proteins. This review is summarizing and focusing on the molecular and functional analysis of pneumococcal serine proteases, thereby discussing their contribution to pathogenesis.


Asunto(s)
Otitis Media , Infecciones Neumocócicas , Humanos , Serina Endopeptidasas/genética , Streptococcus pneumoniae/genética , Subtilisina , Tripsina
5.
Front Biosci (Landmark Ed) ; 26(10): 740-751, 2021 10 30.
Artículo en Inglés | MEDLINE | ID: mdl-34719202

RESUMEN

Objectives: To quantify the integrated levels of ACE2 and TMPRSS2, the two well-recognized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry-related genes, and to further identify key factors contributing to SARS-CoV-2 susceptibility in head and neck squamous cell carcinoma (HNSC). Methods: We developed a metric of the potential for tissue infected with SARS-CoV-2 ("TPSI") based on ACE2 and TMPRSS2 transcript levels and compared TPSI levels between tumor and matched normal tissues across 11 tumor types. For further analysis of HNSC, weighted gene co-expression network analysis (WGCNA), functional analysis, and single sample gene set enrichment analysis (ssGSEA) were conducted to investigate TPSI-relevant biological processes and their relationship with the immune landscape. TPSI-related factors were identified from clinical and mutational domains, followed by lasso regression to determine their relative effects on TPSI levels. Results: TPSI levels in tumors were generally lower than in the normal tissues. In HNSC, the genes highly associated with TPSI were enriched in viral entry-related processes, and TPSI levels were positively correlated with both eosinophils and T helper 17 (Th17) cell infiltration. Furthermore, the site of onset, human papillomaviruses (HPV) status, and nuclear receptor binding SET domain protein 1 (NSD1) mutations were identified as the most important factors shaping TPSI levels. Conclusions: This study identified the infection risk of SARS-CoV-2 between tumor and normal tissues, and provided evidence for the risk stratification of HNSC.


Asunto(s)
Enzima Convertidora de Angiotensina 2/genética , COVID-19/genética , Carcinoma de Células Escamosas/genética , Neoplasias de Cabeza y Cuello/genética , Serina Endopeptidasas/genética , Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/metabolismo , COVID-19/virología , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/virología , Humanos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Serina Endopeptidasas/metabolismo , Internalización del Virus
8.
Proc Natl Acad Sci U S A ; 118(43)2021 10 26.
Artículo en Inglés | MEDLINE | ID: mdl-34635581

RESUMEN

The host cell serine protease TMPRSS2 is an attractive therapeutic target for COVID-19 drug discovery. This protease activates the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and of other coronaviruses and is essential for viral spread in the lung. Utilizing rational structure-based drug design (SBDD) coupled to substrate specificity screening of TMPRSS2, we have discovered covalent small-molecule ketobenzothiazole (kbt) TMPRSS2 inhibitors which are structurally distinct from and have significantly improved activity over the existing known inhibitors Camostat and Nafamostat. Lead compound MM3122 (4) has an IC50 (half-maximal inhibitory concentration) of 340 pM against recombinant full-length TMPRSS2 protein, an EC50 (half-maximal effective concentration) of 430 pM in blocking host cell entry into Calu-3 human lung epithelial cells of a newly developed VSV-SARS-CoV-2 chimeric virus, and an EC50 of 74 nM in inhibiting cytopathic effects induced by SARS-CoV-2 virus in Calu-3 cells. Further, MM3122 blocks Middle East respiratory syndrome coronavirus (MERS-CoV) cell entry with an EC50 of 870 pM. MM3122 has excellent metabolic stability, safety, and pharmacokinetics in mice, with a half-life of 8.6 h in plasma and 7.5 h in lung tissue, making it suitable for in vivo efficacy evaluation and a promising drug candidate for COVID-19 treatment.


Asunto(s)
Benzotiazoles/farmacología , COVID-19/tratamiento farmacológico , Oligopéptidos/farmacología , SARS-CoV-2/efectos de los fármacos , Serina Endopeptidasas/genética , Animales , Benzamidinas/química , Benzotiazoles/farmacocinética , COVID-19/genética , COVID-19/virología , Línea Celular , Diseño de Fármacos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/virología , Ésteres/química , Guanidinas/química , Humanos , Pulmón/efectos de los fármacos , Pulmón/virología , Ratones , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Oligopéptidos/farmacocinética , SARS-CoV-2/patogenicidad , Serina Endopeptidasas/efectos de los fármacos , Serina Endopeptidasas/ultraestructura , Bibliotecas de Moléculas Pequeñas/farmacología , Especificidad por Sustrato/efectos de los fármacos , Internalización del Virus/efectos de los fármacos
9.
Eur J Pharmacol ; 912: 174548, 2021 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-34606834

RESUMEN

The importance of sex differences is increasingly acknowledged in the incidence and treatment of disease. Accumulating clinical evidence demonstrates that sex differences are noticeable in COVID-19, and the prevalence, severity, and mortality rate of COVID-19 are higher among males than females. Sex-related genetic and hormonal factors and immunological responses may underlie the sex bias in COVID-19 patients. Angiotensin-converting enzyme 2 (ACE2) and transmembrane protease/serine subfamily member 2 (TMPRSS2) are essential proteins involved in the cell entry of SARS-CoV-2. Since ACE2 is encoded on the X-chromosome, a double copy of ACE2 in females may compensate for virus-mediated downregulation of ACE2, and thus ACE2-mediated cellular protection is greater in females. The X chromosome also contains the largest immune-related genes leading females to develop more robust immune responses than males. Toll-like receptor-7 (TLR-7), one of the key players in innate immunity, is linked to sex differences in autoimmunity and vaccine efficacy, and its expression is greater in females. Sex steroids also affect immune cell function. Estrogen contributes to higher CD4+ and CD8+ T cell activation levels, and females have more B cells than males. Sex differences not only affect the severity and progression of the disease, but also alter the efficacy of pharmacological treatment and adverse events related to the drugs/vaccines used against COVID-19. Administration of different drugs/vaccines in different doses or intervals may be useful to eliminate sex differences in efficacy and side/adverse effects. It should be noted that studies should include sex-specific analyses to develop further sex-specific treatments for COVID-19.


Asunto(s)
COVID-19/etiología , COVID-19/genética , Predisposición Genética a la Enfermedad/genética , Adulto , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/inmunología , Estrógenos/genética , Estrógenos/inmunología , Femenino , Humanos , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Masculino , Persona de Mediana Edad , SARS-CoV-2/inmunología , Serina Endopeptidasas/genética , Serina Endopeptidasas/inmunología , Caracteres Sexuales , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología
11.
Cell Transplant ; 30: 9636897211049814, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34689578

RESUMEN

During the past 18 months as the world dealt with the COVID-19 pandemic, articles published in Cell Transplantation (CT) voiced unique perspectives on the disease which have since been supported by additional research. Intrigued by the variability in COVID-19 severity, CT authors explored the influence of variants in angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) genes, as well as the role of androgen receptors on disease development. Mesenchymal stem cells (MSC) were offered up as a potential COVID-19 therapy because of their immune modulating characteristics and successful use in other acute respiratory diseases. Two CT author groups gave proof of principle when hospitalized COVID-19 patients were infused with MSC after no other interventions seemed to work. MSC treatment reduced disease severity and shortened hospitalization stays. Lastly, CT authors speculated why we are still in the midst of a pandemic and the consequences of disillusioned comfort as we face new emerging variants that may undermine all we have accomplished thus far.


Asunto(s)
COVID-19/inmunología , COVID-19/terapia , Células Madre Mesenquimatosas/citología , Serina Endopeptidasas/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Investigación Biomédica , Trasplante de Células , Citocinas/metabolismo , Hospitalización , Humanos , Sistema Inmunológico , Células Madre Mesenquimatosas/metabolismo , Peptidil-Dipeptidasa A/genética , Publicaciones , Receptores Androgénicos/metabolismo , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad
12.
Nutrients ; 13(10)2021 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-34684358

RESUMEN

BACKGROUND: Obesity increases the severity of SARS-CoV-2 outcomes. Thus, this study tested whether obesogenic and ketogenic diets distinctly affect SARS-CoV-2 entry proteins and the renin-angiotensin system (RAS) in rat pulmonary and cardiac tissues. METHODS: Male Sprague-Dawley rats were fed either standard chow (SC), a high-fat sucrose-enriched diet (HFS), or a ketogenic diet (KD) for 16 weeks. Afterwards, levels of angiotensin converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), RAS components, and inflammatory genes were measured in the lungs and hearts of these animals. RESULTS: In the lungs, HFS elevated ACE2 and TMPRSS2 levels relative to SC diet, whereas the KD lowered the levels of these proteins and the gene expressions of toll-like receptor 4 and interleukin-6 receptor relative to HFS. The diets did not alter ACE2 and TMPRSS2 in the heart, although ACE2 was more abundant in heart than lung tissues. CONCLUSION: Diet-induced obesity increased the levels of viral entry proteins in the lungs, providing a mechanism whereby SARS-CoV-2 infectivity can be enhanced in obese individuals. Conversely, by maintaining low levels of ACE2 and TMPRSS2 and by exerting an anti-inflammatory effect, the KD can potentially attenuate the severity of infection and migration of SARS-CoV-2 to other ACE2-expressing tissues.


Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/patología , Dieta Alta en Grasa/efectos adversos , Dieta Cetogénica/métodos , Pulmón/metabolismo , Miocardio/metabolismo , Serina Endopeptidasas/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Animales , Biomarcadores/metabolismo , COVID-19/complicaciones , COVID-19/metabolismo , Modelos Animales de Enfermedad , Masculino , Obesidad/complicaciones , Obesidad/metabolismo , Ratas , Ratas Sprague-Dawley , Sistema Renina-Angiotensina , SARS-CoV-2 , Serina Endopeptidasas/genética , Internalización del Virus
13.
Biosci Rep ; 41(10)2021 10 29.
Artículo en Inglés | MEDLINE | ID: mdl-34647577

RESUMEN

Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compounds that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2)) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to down-regulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused down-regulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell-based antiviral drug screening assay showed 30-60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggest that these two closely related compounds possess multimodal anti-COVID-19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.


Asunto(s)
Antivirales/farmacología , COVID-19/tratamiento farmacológico , Biología Computacional/métodos , Enzima Convertidora de Angiotensina 2/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/inmunología , COVID-19/inmunología , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos/métodos , Proteínas HSP70 de Choque Térmico/antagonistas & inhibidores , Humanos , Proteínas Mitocondriales/antagonistas & inhibidores , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , SARS-CoV-2/inmunología , Serina Endopeptidasas/inmunología , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacos
14.
In Vivo ; 35(6): 3233-3243, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34697154

RESUMEN

BACKGROUND: Expression of kallikrein-11 (KLK11) has been found to be related to the prognosis of various human cancer types but its physiological functions in the steps of breast cancer (BC) progression are still unknown. MATERIALS AND METHODS: BC and adjacent normal breast tissue samples were collected from 28 patients. KLK11 expression levels were determined by real-time polymerase chain reaction for each sample and associations with known prognostic features were statistically analyzed. RESULTS: Although there was slight up-regulation in tumor tissues overall, significant down-regulation of KLK11 expression in tumor tissue was observed in the elderly and in patients with perineural invasion. Furthermore, tumor size, grade, mitotic score, necrosis, calcification, lymphatic invasion, hormone receptor status and Ki67 expression were associated with altered KLK11 level. CONCLUSION: Changes in expression levels of KLK11, associated with patient characteristics, might be used as complementary data in order to predict clinical outcome and prognosis in BC.


Asunto(s)
Neoplasias de la Mama , Calicreínas/genética , Anciano , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Pronóstico , Serina Endopeptidasas
15.
Int J Biol Sci ; 17(14): 3954-3967, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34671211

RESUMEN

Furin is a proprotein convertase that activates different kinds of regulatory proteins, including SARS-CoV-2 spike protein which contains an additional furin-specific cleavage site. It is essential in predicting cancer patients' susceptibility to SARS-CoV-2 and the disease outcomes due to varying furin expressions in tumor tissues. In this study, we analyzed furin's expression, methylation, mutation rate, functional enrichment, survival rate and COVID-19 outcomes in normal and cancer tissues using online databases, and our IHC. As a result, furin presented with biased expression profiles in normal tissues, showing 12.25-fold higher than ACE2 in the lungs. The furin expression in tumors were significantly increased in ESCA and TGCT, and decreased in DLBC and THYM, indicating furin may play critical mechanistic functions in COVID-19 viral entry into cells in these cancer patients. Line with furin over/downexpression, furin promoter hypo-/hyper-methylation may be the regulatory cause of disease and lead to pathogenesis of ESCA and THYM. Furthermore, presence of FURIN-201 isoform with functional domains (P_proprotein, Peptidase_S8 and S8_pro-domain) is highest in all cancer types in comparison to other isoforms, demonstrating its use in tumorigenesis and SARS-Cov-2 entry into tumor tissues. Furin mutation frequency was highest in UCES, and its mutation might elevate ACE2 expression in LUAD and UCEC, reduce ACE2 expression in COAD, elevate HSPA5 expression in PAAD, and elevate TMPRSS2 expression in BRCA. These results showed that furin mutations mostly increased expression of ACE2, HSPA5, and TMPRSS2 in certain cancers, indicating furin mutations might facilitate COVID-19 cell entry in cancer patients. In addition, high expression of furin was significantly inversely correlated with long overall survival (OS) in LGG and correlated with long OS in COAD and KIRC, indicating that it could be used as a favorable prognostic marker for cancer patients' survival. GO and KEGG demonstrated that furin was mostly enriched in genes for metabolic and biosynthetic processes, retinal dehydrogenase activity, tRNA methyltransferase activity, and genes involving COVID-19, further supporting its role in COVID-19 and cancer metabolism. Moreover, Cordycepin (CD) inhibited furin expression in a dosage dependent manner. Altogether, furin's high expression might not only implies increased susceptibility to SARS-CoV-2 and higher severity of COVID-19 symptoms in cancer patients, but also it highlights the need for cancer treatment and therapy during the COVID-19 pandemic. CD might have a potential to develop an anti-SARS-CoV-2 drug through inhibiting furin expression.


Asunto(s)
Antineoplásicos/uso terapéutico , COVID-19/virología , Desoxiadenosinas/uso terapéutico , Furina/metabolismo , Neoplasias/metabolismo , Antineoplásicos/farmacología , COVID-19/complicaciones , Línea Celular Tumoral , Desoxiadenosinas/farmacología , Susceptibilidad a Enfermedades , Furina/antagonistas & inhibidores , Furina/genética , Humanos , Neoplasias/complicaciones , Isoformas de Proteínas/metabolismo , Serina Endopeptidasas/metabolismo
16.
Biomed Res Int ; 2021: 9982729, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34692848

RESUMEN

The human transmembrane protease serine 2 (TMPRSS2) protein plays an important role in prostate cancer progression. It also facilitates viral entry into target cells by proteolytically cleaving and activating the S protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In the current study, we used different available tools like SIFT, PolyPhen2.0, PROVEAN, SNAP2, PMut, MutPred2, I-Mutant Suite, MUpro, iStable, ConSurf, ModPred, SwissModel, PROCHECK, Verify3D, and TM-align to identify the most deleterious variants and to explore possible effects on the TMPRSS2 stability, structure, and function. The six missense variants tested were evaluated to have deleterious effects on the protein by SIFT, PolyPhen2.0, PROVEAN, SNAP2, and PMut. Additionally, V160M, G181R, R240C, P335L, G432A, and D435Y variants showed a decrease in stability by at least 2 servers; G181R, G432A, and D435Y are highly conserved and identified posttranslational modifications sites (PTMs) for proteolytic cleavage and ADP-ribosylation using ConSurf and ModPred servers. The 3D structure of TMPRSS2 native and mutants was generated using 7 meq as a template from the SwissModeller group, refined by ModRefiner, and validated using the Ramachandran plot. Hence, this paper can be advantageous to understand the association between these missense variants rs12329760, rs781089181, rs762108701, rs1185182900, rs570454392, and rs867186402 and susceptibility to SARS-CoV-2.


Asunto(s)
COVID-19/genética , Mutación Missense , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Sitios de Unión , Biología Computacional/métodos , Evolución Molecular , Predisposición Genética a la Enfermedad , Humanos , Modelos Moleculares , Filogenia , Polimorfismo de Nucleótido Simple , Conformación Proteica , Estabilidad Proteica , Serina Endopeptidasas/metabolismo
17.
Front Immunol ; 12: 743022, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34603330

RESUMEN

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic. The virus primarily affects the lungs where it induces respiratory distress syndrome ranging from mild to acute, however, there is a growing body of evidence supporting its negative effects on other system organs that also carry the ACE2 receptor, such as the placenta. The majority of newborns delivered from SARS-CoV-2 positive mothers test negative following delivery, suggesting that there are protective mechanisms within the placenta. There appears to be a higher incidence of pregnancy-related complications in SARS-CoV-2 positive mothers, such as miscarriage, restricted fetal growth, or still-birth. In this review, we discuss the pathobiology of COVID-19 maternal infection and the potential adverse effects associated with viral infection, and the possibility of transplacental transmission.


Asunto(s)
COVID-19/patología , Placenta/patología , Placenta/virología , Complicaciones Infecciosas del Embarazo/virología , Aborto Espontáneo/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Femenino , Retardo del Crecimiento Fetal/virología , Humanos , Intercambio Materno-Fetal/fisiología , Embarazo , SARS-CoV-2/patogenicidad , Serina Endopeptidasas/metabolismo , Mortinato
18.
Eur J Med Chem ; 225: 113818, 2021 Dec 05.
Artículo en Inglés | MEDLINE | ID: mdl-34492551

RESUMEN

Cathepsin C, an important lysosomal cysteine protease, mediates the maturation process of neutrophil serine proteases, and participates in the inflammation and immune regulation process associated with polymorphonuclear neutrophils. Therefore, cathepsin C is considered to be an attractive target for treating inflammatory diseases. With INS1007 (trade name: brensocatib) being granted a breakthrough drug designation by FDA for the treatment of Adult Non-cystic Fibrosis Bronchiectasis and Coronavirus Disease 2019, the development of cathepsin C inhibitor will attract attentions from medicinal chemists in the future soon. Here, we summarized the research results of cathepsin C as a therapeutic target, focusing on the development of cathepsin C inhibitor, and provided guidance and reference opinions for the upcoming development boom of cathepsin C inhibitor.


Asunto(s)
Antiinflamatorios/química , Catepsina C/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores de Proteasas/química , Antiinflamatorios/uso terapéutico , COVID-19/tratamiento farmacológico , COVID-19/patología , COVID-19/virología , Catepsina C/genética , Catepsina C/metabolismo , Humanos , Enfermedad de Papillon-Lefevre/genética , Enfermedad de Papillon-Lefevre/patología , Inhibidores de Proteasas/metabolismo , Inhibidores de Proteasas/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/patología , SARS-CoV-2/aislamiento & purificación , Serina Endopeptidasas/metabolismo
19.
PLoS One ; 16(9): e0257152, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34559836

RESUMEN

Approximately 5-7% of non-small cell lung cancer (NSCLC) cases harbor an anaplastic lymphoma kinase (ALK) fusion gene and may benefit from ALK inhibitor therapy. To detect ALK fusion genes, we developed a novel test using reverse transcription polymerase chain reaction (RT-PCR) for the ALK kinase domain (KD). Since ALK expression is mostly silenced in the adult with the exception of neuronal tissue, the normal lung tissue, mesothelial lining, and inflammatory cells are devoid of ALK transcript, making ALK KD RT-PCR an ideal surrogate test for ALK fusion transcripts in lung or pleural effusion. The test was designed with a short PCR product (197 bp) to work for both malignant pleural effusion (MPE) and formalin-fixed, paraffin-embedded (FFPE) NSCLC samples. Using ALK IHC as a reference, the sensitivity of the test was 100% for both MPE and FFPE. The specificity was 97.6% for MPE and 97.4% for FFPE. Two false positive cases were found. One was a metastatic brain lesion which should be avoided in the future due to intrinsic ALK expression in the neuronal tissue. The other one resulted from ALK gene amplification. Due to potential false positivity, subsequent confirmation tests such as fluorescence in situ hybridization or multiplex PCR would be preferable. Nevertheless, the test is simple and inexpensive with no false negativity, making it a desirable screening test. It also offers an advantage over multiplex RT-PCR with the capability to detect novel ALK fusions. Indeed through the screening test, we found a novel ALK fusion partner (sperm antigen with calponin homology and coiled-coil domains 1 like gene, SPECC1L) with increased sensitivity to crizotinib in vitro. In summary, a novel RNA-based ALK KD analysis was developed for ALK rearrangement screening in MPE and FFPE specimens of NSCLC. This simple inexpensive test can be implemented as routine diagnostics.


Asunto(s)
Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Detección Precoz del Cáncer , Reordenamiento Génico , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Proteínas de Ciclo Celular/genética , Proliferación Celular/efectos de los fármacos , Estudios de Cohortes , Crizotinib/farmacología , Crizotinib/uso terapéutico , ADN de Neoplasias/genética , Receptores ErbB/genética , Femenino , Formaldehído , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Proteínas Asociadas a Microtúbulos/genética , Persona de Mediana Edad , Adhesión en Parafina , Derrame Pleural Maligno/enzimología , Derrame Pleural Maligno/genética , Serina Endopeptidasas/genética , Fijación del Tejido
20.
J Biol Chem ; 297(4): 101227, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34562451

RESUMEN

TMPRSS13, a member of the type II transmembrane serine protease (TTSP) family, harbors four N-linked glycosylation sites in its extracellular domain. Two of the glycosylated residues are located in the scavenger receptor cysteine-rich (SRCR) protein domain, while the remaining two sites are in the catalytic serine protease (SP) domain. In this study, we examined the role of N-linked glycosylation in the proteolytic activity, autoactivation, and cellular localization of TMPRSS13. Individual and combinatory site-directed mutagenesis of the glycosylated asparagine residues indicated that glycosylation of the SP domain is critical for TMPRSS13 autoactivation and catalytic activity toward one of its protein substrates, the prostasin zymogen. Additionally, SP domain glycosylation-deficient TMPRSS13 displayed impaired trafficking of TMPRSS13 to the cell surface, which correlated with increased retention in the endoplasmic reticulum. Importantly, we showed that N-linked glycosylation was a critical determinant for subsequent phosphorylation of endogenous TMPRSS13. Taken together, we conclude that glycosylation plays an important role in regulating TMPRSS13 activation and activity, phosphorylation, and cell surface localization.


Asunto(s)
Membrana Celular/enzimología , Precursores Enzimáticos/metabolismo , Proteínas de la Membrana/metabolismo , Procesamiento Proteico-Postraduccional , Proteolisis , Serina Endopeptidasas/metabolismo , Animales , Células COS , Membrana Celular/genética , Chlorocebus aethiops , Precursores Enzimáticos/genética , Células HEK293 , Humanos , Proteínas de la Membrana/genética , Dominios Proteicos , Transporte de Proteínas/genética , Serina Endopeptidasas/genética
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