RESUMEN
INTRODUCCIÓN: Un nuevo brote de coronavirus surgió en 2019 en Wuhan, China, causando conmoción en el sistema sanitario de todo el mundo; el Comité Internacional de Taxonomía de Virus lo denominó SARS-CoV-2, agente causante de la enfermedad COVID-19.El espectro de gravedad de la enfermedad es muy amplio: la mayoría de los pacientes no presentan gravedad, pero otros pueden desarrollar neumonías, y la insuficiencia respiratoria aguda es la causa más frecuente de mortalidad. Objetivo: analizar y desarrollar las distintas alternativas terapéuticas aportadas por la Biotecnología para tratar los síntomas de aquellos pacientes con COVID-19. Metodología: se realizó una revisión de la bibliografía disponible, a partir de enero de 2020 en PubMed, acerca de los tratamientos que se encuentran aún en ensayos clínicos y aquellos que cuentan con aprobación bajo uso de emergencia para la enfermedad COVID-19. También se realizaron búsquedas a través de Google y Google Académico para publicaciones de organismos de Salud en referencia a políticas de salud establecidas para la terapéutica durante dicha pandemia. Resultados: este trabajo aborda las nuevas alternativas terapéuticas para COVID-19 derivadas de la Biotecnología, que se encuentran tanto en uso como en etapas de ensayos clínicos comprendidos dentro del segmento de los biofármacos y las bioterapias. Se incluye un breve resumen del estatus regulatorio de entidades de salud, el mecanismo de acción de dichas terapias y características generales de cada uno. Se incluyen novedosas bioterapias que se empezaron a implementar para afrontar la pandemia. Conclusiones: la pandemia de coronavirus está poniendo a prueba el sistema sanitario internacional, para brindar soluciones tanto desde el diagnóstico y prevención como para el tratamiento de la población a fin de disminuir la mortalidad. Esto incluyó, obviamente también, al área de la Biotecnología aplicada a la salud, que ha aportado en los tres aspectos mencionados; el presente trabajo se centra en las respuestas de tipo terapéutico que ha brindado y que están comercializadas o en fases clínicas. (AU)
INTRODUCTION: A new coronavirus outbreak emerged in 2019 in Wuhan, China, causing a shock to the healthcare system around the world; the International Committee on Taxonomy of Viruses named it SARS-CoV- 2, the infectious agent of the COVID-19 disease. The spectrum of severity of the disease is very wide, most patients are not serious, but others can develop pneumonia, with acute respiratory failure being the most frequent cause of mortality. Objective: to analyze and develop the different therapeutic alternatives provided by Biotechnology dedicated to Health, to treat the symptoms of those COVID-19 patients who require it, and thus reduce mortality.Methodology: a review of the available literature from January 2020 in PubMed of the treatments that are still in clinical trials and those that have been approved under emergency use for the disease COVID-19 was performed. Searches were also carried out through Google and Google Scholar for publications of Health organizations in reference to health policies established for therapeutics during the mentioned pandemic. Results: this work addresses the new therapeutic alternatives derived from Biotechnology, which are both in use and in stages of clinical trials, to treat patients who developed COVID-19 included within the segment of biopharmaceuticals and biotherapies. A brief summary of the regulatory status of health entities, the mechanism of action of said therapies and general characteristics of each one is included. Innovative biotherapies that began to be implemented to face the pandemic are included. Conclusions: The coronavirus pandemic has driven the international health system to the test, to provide solutions both from the diagnosis, prevention and treatment of the population to reduce the mortality of patients. This obviously also included the area of Biotechnology applied to health, which has contributed in the three aspects mentioned. The present work focuses on the therapeutic responses that it has provided and that are commercialized or in clinical phases. (AU)
Asunto(s)
Humanos , Animales , Productos Biológicos/uso terapéutico , Terapia Biológica/métodos , Corticoesteroides/uso terapéutico , SARS-CoV-2/efectos de los fármacos , COVID-19/tratamiento farmacológico , Antivirales/uso terapéutico , Antivirales/farmacología , Terapia Biológica/clasificación , Terapia Biológica/normas , Biotecnología , Ensayos Clínicos como Asunto , Peptidil-Dipeptidasa A/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Agentes Inmunomoduladores/uso terapéutico , Sueroterapia para COVID-19 , Caballos , Sueros Inmunes/biosíntesis , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
Coronavirus disease 2019 (COVID-19) represents a systemic disease that may cause severe metabolic complications in multiple tissues including liver, kidney, and cardiovascular system. However, the underlying mechanisms and optimal treatment remain elusive. Our study shows that impairment of ACE2 pathway is a key factor linking virus infection to its secondary metabolic sequelae. By using structure-based high-throughput virtual screening and connectivity map database, followed with experimental validations, we identify imatinib, methazolamide, and harpagoside as direct enzymatic activators of ACE2. Imatinib and methazolamide remarkably improve metabolic perturbations in vivo in an ACE2-dependent manner under the insulin-resistant state and SARS-CoV-2-infected state. Moreover, viral entry is directly inhibited by these three compounds due to allosteric inhibition of ACE2 binding to spike protein on SARS-CoV-2. Taken together, our study shows that enzymatic activation of ACE2 via imatinib, methazolamide, or harpagoside may be a conceptually new strategy to treat metabolic sequelae of COVID-19.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Mesilato de Imatinib/uso terapéutico , Enfermedades Metabólicas/tratamiento farmacológico , Metazolamida/uso terapéutico , SARS-CoV-2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19/complicaciones , COVID-19/metabolismo , COVID-19/virología , Células Cultivadas , Chlorocebus aethiops , Regulación hacia Abajo/efectos de los fármacos , Células HEK293 , Células Endoteliales de la Vena Umbilical Humana , Humanos , Mesilato de Imatinib/farmacología , Masculino , Enfermedades Metabólicas/metabolismo , Enfermedades Metabólicas/virología , Metazolamida/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Ratones Transgénicos , SARS-CoV-2/fisiología , Células Vero , Internalización del Virus/efectos de los fármacosRESUMEN
SARS-CoV-2 infection of human cells is initiated by the binding of the viral Spike protein to its cell-surface receptor ACE2. We conducted a targeted CRISPRi screen to uncover druggable pathways controlling Spike protein binding to human cells. Here we show that the protein BRD2 is required for ACE2 transcription in human lung epithelial cells and cardiomyocytes, and BRD2 inhibitors currently evaluated in clinical trials potently block endogenous ACE2 expression and SARS-CoV-2 infection of human cells, including those of human nasal epithelia. Moreover, pharmacological BRD2 inhibition with the drug ABBV-744 inhibited SARS-CoV-2 replication in Syrian hamsters. We also found that BRD2 controls transcription of several other genes induced upon SARS-CoV-2 infection, including the interferon response, which in turn regulates the antiviral response. Together, our results pinpoint BRD2 as a potent and essential regulator of the host response to SARS-CoV-2 infection and highlight the potential of BRD2 as a therapeutic target for COVID-19.
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Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/farmacología , Células Epiteliales/virología , SARS-CoV-2/metabolismo , Factores de Transcripción/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , COVID-19/metabolismo , COVID-19/virología , Línea Celular , Células Epiteliales/metabolismo , Humanos , Glicoproteínas de Membrana/metabolismo , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/patogenicidad , Factores de Transcripción/metabolismo , Tratamiento Farmacológico de COVID-19Asunto(s)
Enzima Convertidora de Angiotensina 2 , Intestinos , Mesalamina , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , COVID-19 , Intestinos/efectos de los fármacos , Intestinos/metabolismo , Mesalamina/farmacología , Ratones , SARS-CoV-2/efectos de los fármacos , Índice de Severidad de la EnfermedadRESUMEN
Chloroquine and hydroxychloroquine have been studied since the early clinical treatment of SARS-CoV-2 outbreak. Considering these two chiral drugs are currently in use as the racemate, high-expression angiotensin-converting enzyme 2 cell membrane chromatography was established for investigating the differences of two paired enantiomers binding to angiotensin-converting enzyme 2 receptor. Molecular docking assay and detection of SARS-CoV-2 spike pseudotyped virus entry into angiotensin-converting enzyme 2-HEK293T cells were also conducted for further investigation. Results showed that each single enantiomer could bind well to angiotensin-converting enzyme 2, but there were differences between the paired enantiomers and corresponding racemate in frontal analysis. R-Chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine. Moreover, each single enantiomer was proved effective compared with the control group; compared with S-chloroquine or the racemate, R-chloroquine showed better inhibitory effects at the same concentration. As for hydroxychloroquine, R-hydroxychloroquine showed better inhibitory effects than S-hydroxychloroquine, but it slightly worse than the racemate. In conclusion, R-chloroquine showed better angiotensin-converting enzyme 2 receptor binding ability and inhibitory effects compared to S-chloroquine/chloroquine (racemate). S-Hydroxychloroquine showed better angiotensin-converting enzyme 2 receptor binding ability than R-hydroxychloroquine/hydroxychloroquine (racemate), while the effect of preventing SARS-CoV-2 pseudovirus from entering cells was weaker than R-hydroxychloroquine/hydroxychloroquine (racemate).
Asunto(s)
Enzima Convertidora de Angiotensina 2/química , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Cloroquina/química , Cloroquina/farmacología , Cromatografía Líquida de Alta Presión/métodos , Hidroxicloroquina/química , Hidroxicloroquina/farmacología , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacología , COVID-19/virología , Membrana Celular/química , Membrana Celular/efectos de los fármacos , Membrana Celular/virología , Células HEK293 , Humanos , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Receptores Virales/antagonistas & inhibidores , Receptores Virales/química , Receptores Virales/efectos de los fármacos , SARS-CoV-2/química , SARS-CoV-2/efectos de los fármacos , Solventes , Estereoisomerismo , Pseudotipado Viral , Internalización del Virus , Tratamiento Farmacológico de COVID-19RESUMEN
Coronavirus disease 19 (COVID-19) is a respiratory illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 pathogenesis causes vascular-mediated neurological disorders via elusive mechanisms. SARS-CoV-2 infects host cells via the binding of viral Spike (S) protein to transmembrane receptor, angiotensin-converting enzyme 2 (ACE2). Although brain pericytes were recently shown to abundantly express ACE2 at the neurovascular interface, their response to SARS-CoV-2 S protein is still to be elucidated. Using cell-based assays, we found that ACE2 expression in human brain vascular pericytes was increased upon S protein exposure. Pericytes exposed to S protein underwent profound phenotypic changes associated with an elongated and contracted morphology accompanied with an enhanced expression of contractile and myofibrogenic proteins, such as α-smooth muscle actin (α-SMA), fibronectin, collagen I, and neurogenic locus notch homolog protein-3 (NOTCH3). On the functional level, S protein exposure promoted the acquisition of calcium (Ca2+) signature of contractile ensheathing pericytes characterized by highly regular oscillatory Ca2+ fluctuations. Furthermore, S protein induced lipid peroxidation, oxidative and nitrosative stress in pericytes as well as triggered an immune reaction translated by activation of nuclear factor-kappa-B (NF-κB) signaling pathway, which was potentiated by hypoxia, a condition associated with vascular comorbidities that exacerbate COVID-19 pathogenesis. S protein exposure combined to hypoxia enhanced the production of pro-inflammatory cytokines involved in immune cell activation and trafficking, namely macrophage migration inhibitory factor (MIF). Using transgenic mice expressing the human ACE2 that recognizes S protein, we observed that the intranasal infection with SARS-CoV-2 rapidly induced hypoxic/ischemic-like pericyte reactivity in the brain of transgenic mice, accompanied with an increased vascular expression of ACE2. Moreover, we found that SARS-CoV-2 S protein accumulated in the intranasal cavity reached the brain of mice in which the nasal mucosa is deregulated. Collectively, these findings suggest that SARS-CoV-2 S protein impairs the vascular and immune regulatory functions of brain pericytes, which may account for vascular-mediated brain damage. Our study provides a better understanding for the mechanisms underlying cerebrovascular disorders in COVID-19, paving the way to develop new therapeutic interventions.
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Enzima Convertidora de Angiotensina 2/metabolismo , Encéfalo/metabolismo , COVID-19/metabolismo , Hipoxia-Isquemia Encefálica/metabolismo , Hipoxia/metabolismo , Inflamación/metabolismo , Pericitos/metabolismo , SARS-CoV-2/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Actinas/metabolismo , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/genética , Animales , Encéfalo/irrigación sanguínea , COVID-19/fisiopatología , Señalización del Calcio , Colágeno Tipo I/metabolismo , Fibronectinas/metabolismo , Humanos , Hipoxia-Isquemia Encefálica/fisiopatología , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/genética , Factores Inhibidores de la Migración de Macrófagos/efectos de los fármacos , Factores Inhibidores de la Migración de Macrófagos/metabolismo , Ratones , Ratones Transgénicos , Músculo Liso Vascular/citología , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/metabolismo , Miofibroblastos , FN-kappa B/efectos de los fármacos , FN-kappa B/metabolismo , Mucosa Nasal , Estrés Nitrosativo , Estrés Oxidativo , Pericitos/citología , Pericitos/efectos de los fármacos , Fenotipo , Receptor Notch3/metabolismo , Receptores de Coronavirus/efectos de los fármacos , Receptores de Coronavirus/genética , Receptores de Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/farmacologíaRESUMEN
BACKGROUND: SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) and neuropilin-1 (NRP1) receptors for entry into cells, and the serine protease TMPRSS2 for S protein priming. Inhibition of protease activity or the engagement with ACE2 and NRP1 receptors has been shown to be an effective strategy for blocking infectivity and viral spreading. Valproic acid (VPA; 2-propylpentanoic acid) is an epigenetic drug approved for clinical use. It produces potent antiviral and anti-inflammatory effects through its function as a histone deacetylase (HDAC) inhibitor. Here, we propose VPA as a potential candidate to tackle COVID-19, in which rapid viral spread and replication, and hyperinflammation are crucial elements. RESULTS: We used diverse cell lines (HK-2, Huh-7, HUVEC, Caco-2, and BEAS-2B) to analyze the effect of VPA and other HDAC inhibitors on the expression of the ACE-2 and NRP-1 receptors and their ability to inhibit infectivity, viral production, and the inflammatory response. Treatment with VPA significantly reduced expression of the ACE2 and NRP1 host proteins in all cell lines through a mechanism mediated by its HDAC inhibitory activity. The effect is maintained after SARS-CoV-2 infection. Consequently, the treatment of cells with VPA before infection impairs production of SARS-CoV-2 infectious viruses, but not that of other ACE2- and NRP1-independent viruses (VSV and HCoV-229E). Moreover, the addition of VPA 1 h post-infection with SARS-CoV-2 reduces the production of infectious viruses in a dose-dependent manner without significantly modifying the genomic and subgenomic messenger RNAs (gRNA and sg mRNAs) or protein levels of N protein. The production of inflammatory cytokines (TNF-α and IL-6) induced by TNF-α and SARS-CoV-2 infection is diminished in the presence of VPA. CONCLUSIONS: Our data showed that VPA blocks three essential processes determining the severity of COVID-19. It downregulates the expression of ACE2 and NRP1, reducing the infectivity of SARS-CoV-2; it decreases viral yields, probably because it affects virus budding or virions stability; and it dampens the triggered inflammatory response. Thus, administering VPA could be considered a safe treatment for COVID-19 patients until vaccines have been rolled out across the world.
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Enzima Convertidora de Angiotensina 2/genética , COVID-19/prevención & control , Epigénesis Genética/fisiología , Neuropilina-1/genética , Receptores Virales/efectos de los fármacos , Ácido Valproico/farmacología , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antivirales/farmacología , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Epigénesis Genética/genética , Humanos , Neuropilina-1/efectos de los fármacos , SARS-CoV-2RESUMEN
It has been proposed that men hospitalised with COVID-19 be treated with oestrogen or progesterone to improve COVID-19 outcomes. Transgender women (male-to-female) are routinely treated with oestrogen or oestrogen +progesterone for feminisation which provides a model for the effect of feminising hormones on testicular tissue. Our goal was to analyse differences in ACE-2 expression in testicles of trans-women taking oestrogen or oestrogen +progesterone. Orchiectomy specimens were collected from trans-women undergoing gender-affirming surgery, who were taking oestrogen or oestrogen+progesterone preoperatively. For controls, we used benign orchiectomy specimens from cis-gender men. All specimens were stained with H&E, Trichrome (fibrosis), insulin-like 3 antibody (Leydig cell) and ACE-2 IHC. Cells per high-powered field were counted by cell type (Leydig, Sertoli and Germ). Stain intensity was rated on a 0-2 scale. On immunohistochemistry staining for Leydig cells and ACE-2 staining, the oestrogen+progesterone cohort had fewer Leydig cells compared with controls. The oestrogen+progesterone cohort also had greater degree of tissue fibrosis compared with controls and the oestrogen cohort. This work supports the hopeful possibility that a short course of progesterone (or oestrogen+progesterone) could downregulate ACE-2 to protect men from COVID-19 infection.
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Enzima Convertidora de Angiotensina 2 , Estrógenos , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/genética , COVID-19 , Estrógenos/farmacología , Femenino , Humanos , Células Intersticiales del Testículo , Masculino , SARS-CoV-2 , TestículoRESUMEN
In the setting of the raging COVID-19 pandemic, the search for innovative therapeutics is desperately sought after. As we learn more about the characteristics and metabolic health of patients and as our understanding of COVID-19 pathophysiology and treatment progresses, so is our understanding of medication effects that might increase disease severity. As of late, ACE inhibitors have been under investigation for a potential increase in illness severity due to ACE2 upregulation. Given our knowledge of other nutrient-pharmaceutical interactions, could the ACE inhibitor impact on COVID be due to something else? In this paper, we discuss the possibility that ACE inhibitors might be affecting COVID-19 patients by causing zinc insufficiency.KEY MESSAGESZinc deficiency caused by chronic ACE inhibitor usage may exacerbate the pathogenicity of COVID-19 in susceptible patients.A multi-center study is needed to assess the zinc levels of patients with COVID-19 who are taking ACE inhibitors and other medications that may result in low zinc levels.
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Enzima Convertidora de Angiotensina 2/metabolismo , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Tratamiento Farmacológico de COVID-19 , Zinc/deficiencia , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/virología , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Estado Nutricional/efectos de los fármacos , Preparaciones Farmacéuticas , Factores de Riesgo , SARS-CoV-2/genética , Índice de Severidad de la Enfermedad , Zinc/sangreRESUMEN
The successive emergences and accelerating spread of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineages and evolved resistance to some ongoing clinical therapeutics increase the risks associated with the coronavirus disease 2019 (COVID-19) pandemic. An urgent intervention for broadly effective therapies to limit the morbidity and mortality of COVID-19 and future transmission events from SARS-related coronaviruses (SARSr-CoVs) is needed. Here, we isolate and humanize an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody (MAb), named h11B11, which exhibits potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages. When administered therapeutically or prophylactically in the hACE2 mouse model, h11B11 alleviates and prevents SARS-CoV-2 replication and virus-induced pathological syndromes. No significant changes in blood pressure and hematology chemistry toxicology were observed after injections of multiple high dosages of h11B11 in cynomolgus monkeys. Analysis of the structures of the h11B11/ACE2 and receptor-binding domain (RBD)/ACE2 complexes shows hindrance and epitope competition of the MAb and RBD for the receptor. Together, these results suggest h11B11 as a potential therapeutic countermeasure against SARS-CoV, SARS-CoV-2, and escape variants.
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Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/inmunología , Anticuerpos Neutralizantes/administración & dosificación , Tratamiento Farmacológico de COVID-19 , SARS-CoV-2/efectos de los fármacos , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , COVID-19/inmunología , COVID-19/mortalidad , COVID-19/virología , Chlorocebus aethiops , Modelos Animales de Enfermedad , Epítopos , Femenino , Células HEK293 , Haplorrinos , Humanos , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Pandemias , SARS-CoV-2/inmunología , SARS-CoV-2/aislamiento & purificación , Células Vero , Activación ViralRESUMEN
BACKGROUND AND OBJECTIVE: Coronavirus disease 2019 is a novel disease caused by the severe acute respiratory syndrome coronavirus (SARS-CoV)-2 virus. It was first detected in December 2019 and has since been declared a pandemic causing millions of deaths worldwide. Therefore, there is an urgent need to develop effective therapeutics against coronavirus disease 2019. A critical step in the crosstalk between the virus and the host cell is the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the peptidase domain of the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of host cells. METHODS: An in silico approach was employed to design a 13-amino acid peptide inhibitor (13AApi) against the RBD of the SARS-CoV-2 spike protein. Its binding specificity for RBD was confirmed by molecular docking using pyDockWEB, ClusPro 2.0, and HDOCK web servers. The stability of 13AApi and the SARS-CoV-2 spike protein complex was determined by molecular dynamics simulation using the GROMACS program while the physicochemical and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of 13AApi were determined using the ExPASy tool and pkCSM server. Finally, in vitro validation of the inhibitory activity of 13AApi against the spike protein was performed by an enzyme-linked immunosorbent assay. RESULTS: In silico analyses indicated that the 13AApi could bind to the RBD of the SARS-CoV-2 spike protein at the ACE2 binding site with high affinity. In vitro experiments validated the in silico findings, showing that 13AApi could significantly block the RBD of the SARS-CoV-2 spike protein. CONCLUSIONS: Blockage of binding of the SARS-CoV-2 spike protein with ACE2 in the presence of the 13AApi may prevent virus entry into host cells. Therefore, the 13AApi can be utilized as a promising therapeutic agent to combat coronavirus disease 2019.
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Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antivirales/farmacología , Péptidos/farmacología , Glicoproteína de la Espiga del Coronavirus/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/metabolismo , Antivirales/farmacocinética , Antivirales/toxicidad , Sitios de Unión , Simulación por Computador , Diseño de Fármacos , Humanos , Modelos Moleculares , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Estructura Molecular , Péptidos/farmacocinética , Péptidos/toxicidad , Unión Proteica/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/metabolismo , Especificidad por SustratoRESUMEN
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019, it binds to angiotensin-converting enzyme 2 (ACE2) to enter into human cells. The expression level of ACE2 potentially determine the susceptibility and severity of COVID-19, it is thus of importance to understand the regulatory mechanism of ACE2 expression. Tripartite motif containing 28 (TRIM28) is known to be involved in multiple processes including antiviral restriction, endogenous retrovirus latency and immune response, it is recently reported to be co-expressed with SARS-CoV-2 receptor in type II pneumocytes; however, the roles of TRIM28 in ACE2 expression and SARS-CoV-2 cell entry remain unclear. This study showed that knockdown of TRIM28 induces ACE2 expression and increases pseudotyped SARS-CoV-2 cell entry of A549 cells and primary pulmonary alveolar epithelial cells (PAEpiCs). In a co-culture model of NK cells and lung epithelial cells, our results demonstrated that NK cells inhibit TRIM28 and promote ACE2 expression in lung epithelial cells, which was partially reversed by depletion of interleukin-2 and blocking of granzyme B in the co-culture medium. Furthermore, TRIM28 knockdown enhanced interferon-γ (IFN-γ)- induced ACE2 expression through a mechanism involving upregulating IFN-γ receptor 2 (IFNGR2) in both A549 and PAEpiCs. The upregulated ACE2 induced by TRIM28 knockdown and co-culture of NK cells was partially reversed by dexamethasone in A549 cells. Our study identified TRIM28 as a novel regulator of ACE2 expression and SARS-CoV-2 cell entry.
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Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antivirales/farmacología , SARS-CoV-2/patogenicidad , Proteína 28 que Contiene Motivos Tripartito/inmunología , Internalización del Virus/efectos de los fármacos , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/virología , Enzima Convertidora de Angiotensina 2/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/virología , Humanos , Pulmón/metabolismo , Pulmón/virología , Peptidil-Dipeptidasa A/metabolismo , Proteína 28 que Contiene Motivos Tripartito/efectos de los fármacosRESUMEN
Nephrotoxicity is a rapid deterioration of kidney function due to exposure to nephrotoxic drugs as gentamicin. Gentamicin increases the generation of reactive oxygen species (ROS) leading to inflammatory responses and nuclear factor-κB (NF-κB) activation. The renal renin-angiotensin system (RAS) is considered a crucial regulator for physiological homeostasis and disease progression through the classic ACE/Ang-II/AT1 axis and its antagonist, ACE2/Ang-(1-7)/Mas axis which exerts an important role in the kidney. The present study evaluates the protective effects of the angiotensin-converting enzyme 2 (ACE2) activator; xanthenone; against experimental nephrotoxicity induced by gentamicin. Rats were divided into 4 groups, normal control, xanthenone (2 mg/kg, s.c), gentamicin (100 mg/kg, i.p. for one week) and xanthenone + gentamicin groups. Blood urea nitrogen (BUN) and serum creatinine levels were measured. The kidney tissues were used for estimating glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), NF-κB, Angiotensin II (AngII), and Ang-(1-7). In addition, histopathological examination and Western blot analysis of ACE2 expression were done. Xanthenone significantly restored serum levels of BUN and creatinine. Xanthenone exerted significant antioxidant effect as revealed by increased GSH content and SOD activity together with reduced MDA content. It exerted anti-inflammatory effect by significant reduction in TNF-α, NF-κB and IL-6 expression compared to gentamicin group. Xanthenone increased Ang-(1-7) and ACE2 expression while significantly decreased Ang-II expression. Histopathologically, xanthenone markedly counteracted gentamicin-induced renal aberrations. Activation of ACE2/Ang-(1-7) by xanthenone produced significant antioxidant and anti-inflammatory effects that counteracted gentamicin-induced nephrotoxicity.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Angiotensina I/metabolismo , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Gentamicinas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Transducción de Señal/efectos de los fármacos , Xantonas/farmacología , Lesión Renal Aguda/prevención & control , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Western Blotting , Interleucinas/metabolismo , Masculino , Ratas , Ratas WistarRESUMEN
In the brain, aminopeptidase A (APA), a membrane-bound zinc metalloprotease, generates angiotensin III from angiotensin II. Brain angiotensin III exerts a tonic stimulatory effect on the control of blood pressure (BP) in hypertensive rats and increases vasopressin release. Blocking brain angiotensin III formation by the APA inhibitor prodrug RB150/firibastat normalizes arterial BP in hypertensive deoxycorticosterone acetate (DOCA)-salt rats without inducing angiotensin II accumulation. We therefore hypothesized that another metabolic pathway of brain angiotensin II, such as the conversion of angiotensin II into angiotensin 1-7 (Ang 1-7) by angiotensin-converting enzyme 2 (ACE2) might be activated following brain APA inhibition. We found that the intracerebroventricular (icv) administration of RB150/firibastat in conscious DOCA-salt rats both inhibited brain APA activity and induced an increase in brain ACE2 activity. Then, we showed that the decreases in BP and vasopressin release resulting from brain APA inhibition with RB150/firibastat were reduced if ACE2 was concomitantly inhibited by MLN4760, a potent ACE2 inhibitor, or if the Mas receptor (MasR) was blocked by A779, a MasR antagonist. Our findings suggest that in the brain, the increase in ACE2 activity resulting from APA inhibition by RB150/firibastat treatment, subsequently increasing Ang 1-7 and activating the MasR while blocking angiotensin III formation, contributes to the antihypertensive effect and the decrease in vasopressin release induced by RB150/firibastat. RB150/firibastat treatment constitutes an interesting therapeutic approach to improve BP control in hypertensive patients by inducing in the brain renin-angiotensin system, hyperactivity of the beneficial ACE2/Ang 1-7/MasR axis while decreasing that of the deleterious APA/Ang II/Ang III/ATI receptor axis.
Asunto(s)
Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antihipertensivos/farmacología , Disulfuros/farmacología , Glutamil Aminopeptidasa/antagonistas & inhibidores , Hipertensión/fisiopatología , Ácidos Sulfónicos/farmacología , Angiotensina III/metabolismo , Enzima Convertidora de Angiotensina 2/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Acetato de Desoxicorticosterona/administración & dosificación , Modelos Animales de Enfermedad , Glutamil Aminopeptidasa/metabolismo , Hipertensión/inducido químicamente , Masculino , Ratones , Ratas Wistar , Cloruro de Sodio DietéticoRESUMEN
The epidemic due to the novel coronavirus (SARS-CoV-2) is now a global concern, posing a severe threat to the health of populations. At present, all countries in the world are stepping up the development of vaccines and antiviral agents to prevent the infection and further transmission of SARS-CoV-2. An in-depth investigation of the target organs and pathogenesis regarding SARS-CoV-2 infection will be beneficial for virus therapy. Besides pulmonary injury, SARS-CoV-2 also causes cardiac injury, but the exact mechanisms are unclear. This review summarizes the essential structural characteristics of SARS-CoV-2 and angiotensin-converting enzyme 2 (ACE2), describes the cardiac manifestations following SARS-CoV-2 infection, and explores the mechanisms of cardiac injury targeting ACE2 after the viral invasion. We aim to help the timely detection of related symptoms and implementation of therapeutic measures by clinicians for SARS-CoV-2 infection.
Asunto(s)
Enzima Convertidora de Angiotensina 2/efectos de los fármacos , COVID-19/fisiopatología , Cardiopatías/etiología , SARS-CoV-2/patogenicidad , Enzima Convertidora de Angiotensina 2/fisiología , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/complicaciones , COVID-19/virología , Sistemas de Liberación de Medicamentos , Diagnóstico Precoz , Genoma Viral , Cardiopatías/diagnóstico , Humanos , SARS-CoV-2/genética , SARS-CoV-2/aislamiento & purificación , Tratamiento Farmacológico de COVID-19RESUMEN
Coronavirus disease-2019 (COVID-19), caused by SARS-CoV-2, has led to the ongoing global pandemic. Although most patients experience no or only mild symptoms, some patients can develop severe illness, such as progressive pneumonia, acute respiratory distress syndrome, secondary hemophagocytic lymphohistiocytosis and multiple organ failure caused by cytokine release syndrome. A majority of COVID-19 patients also develop gastrointestinal symptoms. These can present special challenges to the management of patients with inflammatory bowel disease (IBD) due to potential interactions between the immune response related to SARS-CoV-2 infection and dysregulated immunity associated with IBD. In this context, the pathogenesis of COVID-19 is reviewed in order to address these questions regarding immune interactions between COVID-19 and IBD.
Asunto(s)
COVID-19/epidemiología , COVID-19/fisiopatología , Inmunidad/fisiología , Enfermedades Inflamatorias del Intestino/epidemiología , Enfermedades Inflamatorias del Intestino/fisiopatología , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Enzima Convertidora de Angiotensina 2/inmunología , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , COVID-19/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/epidemiología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/fisiopatología , Humanos , Inmunidad/efectos de los fármacos , Inmunosupresores/farmacología , Inmunosupresores/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/inmunología , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/inmunología , Tratamiento Farmacológico de COVID-19RESUMEN
After initially hypothesizing a positive relationship between use of renin-angiotensin-aldosterone system inhibitors and risk of coronavirus disease 2019 (COVID-19), more recent evidence suggests negative associations. We examined whether COVID-19 risk differs according to antihypertensive drug class in patients treated by ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) compared with calcium channel blockers (CCBs). Three exclusive cohorts of prevalent ACE inhibitors, ARB and CCB users, aged 18 to 80 years, from the French National Health Insurance databases were followed from February 15, 2020 to June 7, 2020. We excluded patients with a history of diabetes, known cardiovascular disease, chronic renal failure, or chronic respiratory disease during the previous 5 years, to only consider patients treated for uncomplicated hypertension and to limit indication bias. The primary end point was time to hospitalization for COVID-19. The secondary end point was time to intubation/death during a hospital stay for COVID-19. In a population of almost 2 million hypertensive patients (ACE inhibitors: 566 023; ARB: 958 227; CCB: 358 306) followed for 16 weeks, 2338 were hospitalized and 526 died or were intubated for COVID-19. ACE inhibitors and ARBs were associated with a lower risk of COVID-19 hospitalization compared with CCBs (hazard ratio, 0.74 [95% CI, 0.65-0.83] and 0.84 [0.76-0.93], respectively) and a lower risk of intubation/death. Risks were slightly lower for ACE inhibitor users than for ARB users. This large observational study may suggest a lower COVID-19 risk in hypertensive patients treated over a long period with ACE inhibitors or ARBs compared with CCBs. These results, if confirmed, tend to contradict previous hypotheses and raise new hypotheses.
Asunto(s)
Antagonistas de Receptores de Angiotensina/efectos adversos , Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Antihipertensivos/efectos adversos , COVID-19/epidemiología , Hipertensión/tratamiento farmacológico , Pandemias , Receptores Virales/efectos de los fármacos , SARS-CoV-2/fisiología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores de Angiotensina/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , COVID-19/etiología , Bloqueadores de los Canales de Calcio/efectos adversos , Bloqueadores de los Canales de Calcio/uso terapéutico , Comorbilidad , Susceptibilidad a Enfermedades , Utilización de Medicamentos , Femenino , Estudios de Seguimiento , Francia/epidemiología , Mortalidad Hospitalaria , Hospitalización/estadística & datos numéricos , Humanos , Hipertensión/epidemiología , Intubación Intratraqueal/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
Over the past two decades, deadly coronaviruses, with the most recent being the severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) 2019 pandemic, have majorly challenged public health. The path for virus invasion into humans and other hosts is mediated by host-pathogen interactions, specifically virus-receptor binding. An in-depth understanding of the virus-receptor binding mechanism is a prerequisite for the discovery of vaccines, antibodies, and small-molecule inhibitors that can interrupt this interaction and prevent or cure infection. In this review, we discuss the viral entry mechanism, the known structural aspects of virus-receptor interactions (SARS-CoV-2 S/humanACE2, SARS-CoV S/humanACE2, and MERS-CoV S/humanDPP4), the key protein domains and amino acid residues involved in binding, and the small-molecule inhibitors and other drugs that have (as of June 2020) exhibited therapeutic potential. Specifically, we review the potential clinical utility of two transmembrane serine protease 2 (TMPRSS2)-targeting protease inhibitors, nafamostat mesylate and camostat mesylate, as well as two novel potent fusion inhibitors and the repurposed Ebola drug, remdesivir, which is specific to RNA-dependent RNA polymerase, against human coronaviruses, including SARS-CoV-2.
Asunto(s)
Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antivirales/farmacología , Antivirales/uso terapéutico , Tratamiento Farmacológico de COVID-19 , Receptores Virales/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas , Humanos , Inhibidores de Proteasas/uso terapéuticoRESUMEN
The recent emergence of the novel pathogenic coronavirus disease 2019 (COVID-19) is responsible for a worldwide pandemic. In sight of this, there has been growing interest in the use of chloroquine (CQ) and hydroxychloroquine (HCQ) as potential treatments. In this study, we use angiotensin converting enzyme 2 (ACE2) over-expressed cell membrane chromatography (CMC) to study the interaction of CQ and HCQ with ACE2 receptor. Both CQ and HCQ were retained on the ACE2/CMC column. Then we analyzed the binding character of CQ and HCQ to ACE2 by CMC frontal analysis, ionic force investigation and competitive binding experiment. Results showed that CQ and HCQ KD values obtained from the CMC frontal analysis method were 8.22(±0.61) × 10-7 M and 11.70(±2.44) × 10-7 M. Compare to CQ, HCQ has the weaker affinity with ACE2. The action force of CQ, HCQ and ACE2 is mainly ionic force. CQ and HCQ have different degrees of competitive binding relationship with ACE2. Our study revealed the interaction of CQ and HCQ with ACE2 receptor, which provides new insights for the use of CQ and HCQ in the treatment of COVID-19. Moreover, this biomimetic drug screening method is expected to open the door for rapid targeting and separating bioactive ingredients active towards ACE2 receptor.
Asunto(s)
Enzima Convertidora de Angiotensina 2/efectos de los fármacos , Antimaláricos/farmacología , Membrana Celular/química , Cloroquina/farmacología , Hidroxicloroquina/farmacología , Enzima Convertidora de Angiotensina 2/biosíntesis , Unión Competitiva/efectos de los fármacos , COVID-19/metabolismo , Cromatografía/métodos , Humanos , Modelos Moleculares , Simulación del Acoplamiento MolecularRESUMEN
The causes of the increased risk of severe coronavirus disease 2019 (COVID-19) in people with diabetes are unclear. It has been speculated that renin-angiotensin system (RAS) blockers may promote COVID-19 by increasing ACE2, which severe acute respiratory syndrome coronavirus 2 uses to enter host cells, along with the host protease TMPRSS2. Taking a reverse translational approach and by combining in situ hybridization, primary cell isolation, immunoblotting, quantitative RT-PCR, and liquid chromatography-tandem mass spectrometry, we studied lung and kidney ACE2 and TMPRSS2 in diabetic mice mimicking host factors linked to severe COVID-19. In healthy young mice, neither the ACE inhibitor ramipril nor the AT1 receptor blocker telmisartan affected lung or kidney ACE2 or TMPRSS2, except for a small increase in kidney ACE2 protein with ramipril. In contrast, mice with comorbid diabetes (aging, high-fat diet, and streptozotocin-induced diabetes) had heightened lung ACE2 and TMPRSS2 protein levels and increased lung ACE2 activity. None of these parameters were affected by RAS blockade. ACE2 was similarly upregulated in the kidneys of mice with comorbid diabetes compared with aged controls, whereas TMPRSS2 (primarily distal nephron) was highest in telmisartan-treated animals. Upregulation of lung ACE2 activity in comorbid diabetes may contribute to an increased risk of severe COVID-19. This upregulation is driven by comorbidity and not by RAS blockade.