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1.
Endocr Rev ; 41(3)2020 06 01.
Artículo en Inglés | MEDLINE | ID: covidwho-1110054

RESUMEN

Individuals with diabetes are at increased risk for bacterial, mycotic, parasitic, and viral infections. The severe acute respiratory syndrome (SARS)-CoV-2 (also referred to as COVID-19) coronavirus pandemic highlights the importance of understanding shared disease pathophysiology potentially informing therapeutic choices in individuals with type 2 diabetes (T2D). Two coronavirus receptor proteins, angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-4 (DPP4) are also established transducers of metabolic signals and pathways regulating inflammation, renal and cardiovascular physiology, and glucose homeostasis. Moreover, glucose-lowering agents such as the DPP4 inhibitors, widely used in subjects with T2D, are known to modify the biological activities of multiple immunomodulatory substrates. Here, we review the basic and clinical science spanning the intersections of diabetes, coronavirus infections, ACE2, and DPP4 biology, highlighting clinical relevance and evolving areas of uncertainty underlying the pathophysiology and treatment of T2D in the context of coronavirus infection.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Neumonía Viral/complicaciones , Animales , Infecciones por Coronavirus/metabolismo , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Tracto Gastrointestinal/metabolismo , Humanos , Insulina/uso terapéutico , Pulmón/metabolismo , Obesidad/complicaciones , Obesidad/metabolismo , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/metabolismo , Receptores Virales/metabolismo , Factores de Riesgo , Serina Endopeptidasas/metabolismo
2.
JCI Insight ; 6(6)2021 03 22.
Artículo en Inglés | MEDLINE | ID: covidwho-1088356

RESUMEN

Regulatory T (Treg) cells orchestrate resolution and repair of acute lung inflammation and injury after viral pneumonia. Compared with younger patients, older individuals experience impaired recovery and worse clinical outcomes after severe viral infections, including influenza and SARS coronavirus 2 (SARS-CoV-2). Whether age is a key determinant of Treg cell prorepair function after lung injury remains unknown. Here, we showed that aging results in a cell-autonomous impairment of reparative Treg cell function after experimental influenza pneumonia. Transcriptional and DNA methylation profiling of sorted Treg cells provided insight into the mechanisms underlying their age-related dysfunction, with Treg cells from aged mice demonstrating both loss of reparative programs and gain of maladaptive programs. Strategies to restore youthful Treg cell functional programs could be leveraged as therapies to improve outcomes among older individuals with severe viral pneumonia.


Asunto(s)
Envejecimiento/fisiología , Virus de la Influenza A , Gripe Humana/patología , Pulmón/patología , Neumonía Viral/patología , Linfocitos T Reguladores/patología , Factores de Edad , Envejecimiento/metabolismo , Animales , /metabolismo , /virología , Humanos , Gripe Humana/complicaciones , Gripe Humana/metabolismo , Gripe Humana/virología , Pulmón/metabolismo , Ratones Endogámicos C57BL , Neumonía Viral/etiología , Neumonía Viral/metabolismo , Neumonía Viral/virología , Linfocitos T Reguladores/metabolismo
3.
Sci Rep ; 10(1): 14214, 2020 08 26.
Artículo en Inglés | MEDLINE | ID: covidwho-1065924

RESUMEN

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple 500 ns or 1 µs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV-2 and SARS-CoV utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 S protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493 and Gln498 of SARS-CoV-2 and Asp38, Glu35 and Lys353 of ACE2 were observed, which were absent in the ACE2-SARS-CoV interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/metabolismo , Neumonía Viral/virología , Virus del SRAS/fisiología , Síndrome Respiratorio Agudo Grave/virología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Secuencia Conservada , Interacciones Huésped-Patógeno , Humanos , Modelos Moleculares , Pandemias , Peptidil-Dipeptidasa A/química , Unión Proteica , Conformación Proteica , Glicoproteína de la Espiga del Coronavirus/química
5.
Endocrinol Metab (Seoul) ; 35(2): 197-205, 2020 06.
Artículo en Inglés | MEDLINE | ID: covidwho-1004777

RESUMEN

The world is entering an era of disaster and chaos due to coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2. Since its first emergence in December 2019 in Wuhan, China, COVID-19 has swept through Asia and propagated throughout the world to Europe and North America. As of April 13, 1,773,084 people were infected and 111,652 people had died from COVID-19 globally, and new record levels of infection are being reported every day. Based on the data that have been amassed so far, the primary risk factors for a severe disease course or even mortality from COVID-19 are underlying diseases such as diabetes and hypertension. As the global prevalence of diabetes continues to increase, patients with endocrine diseases such as diabetes mellitus and those who are on long-term corticosteroid therapy due to adrenal insufficiency or hypopituitarism are at risk for a poor prognosis of COVID-19. As endocrinologists, we would like to briefly review the current knowledge about the relationship between COVID-19 and endocrine diseases and to discuss what we can do for the safety and health of our patients with endocrine diseases in this globally threatening situation.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/metabolismo , Enfermedades del Sistema Endocrino/epidemiología , Enfermedades del Sistema Endocrino/metabolismo , Endocrinólogos/tendencias , Neumonía Viral/epidemiología , Neumonía Viral/metabolismo , Infecciones por Coronavirus/diagnóstico , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Enfermedades del Sistema Endocrino/diagnóstico , Humanos , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hipertensión/metabolismo , Pandemias , Neumonía Viral/diagnóstico , Factores de Riesgo
6.
Viruses ; 12(10)2020 09 26.
Artículo en Inglés | MEDLINE | ID: covidwho-982816

RESUMEN

In a short time, the COVID-19 pandemic has left the world with over 25 million cases and staggering death tolls that are still rising. Treatments for SARS-CoV-2 infection are desperately needed as there are currently no approved drug therapies. With limited knowledge of viral mechanisms, a network controllability method of prioritizing existing drugs for repurposing efforts is optimal for quickly moving through the drug approval pipeline using limited, available, virus-specific data. Based on network topology and controllability, 16 proteins involved in translation, cellular transport, cellular stress, and host immune response are predicted as regulators of the SARS-CoV-2 infected cell. Of the 16, eight are prioritized as possible drug targets where two, PVR and SCARB1, are previously unexplored. Known compounds targeting these genes are suggested for viral inhibition study. Prioritized proteins in agreement with previous analysis and viral inhibition studies verify the ability of network controllability to predict biologically relevant candidates.


Asunto(s)
Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Reposicionamiento de Medicamentos/métodos , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/aislamiento & purificación , Betacoronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Aprobación de Drogas , Sistemas de Liberación de Medicamentos , Interacciones Huésped-Patógeno , Humanos , Pandemias , Neumonía Viral/metabolismo , Neumonía Viral/virología , Mapas de Interacción de Proteínas/efectos de los fármacos , Receptores Virales/genética , Receptores Virales/metabolismo , Receptores Depuradores de Clase B/metabolismo , Integración Viral
7.
JCI Insight ; 5(11)2020 06 04.
Artículo en Inglés | MEDLINE | ID: covidwho-980226

RESUMEN

In severe cases of coronavirus disease 2019 (COVID-19), viral pneumonia progresses to respiratory failure. Neutrophil extracellular traps (NETs) are extracellular webs of chromatin, microbicidal proteins, and oxidant enzymes that are released by neutrophils to contain infections. However, when not properly regulated, NETs have the potential to propagate inflammation and microvascular thrombosis - including in the lungs of patients with acute respiratory distress syndrome. We now report that sera from patients with COVID-19 have elevated levels of cell-free DNA, myeloperoxidase-DNA (MPO-DNA), and citrullinated histone H3 (Cit-H3); the latter 2 are specific markers of NETs. Highlighting the potential clinical relevance of these findings, cell-free DNA strongly correlated with acute-phase reactants, including C-reactive protein, D-dimer, and lactate dehydrogenase, as well as absolute neutrophil count. MPO-DNA associated with both cell-free DNA and absolute neutrophil count, while Cit-H3 correlated with platelet levels. Importantly, both cell-free DNA and MPO-DNA were higher in hospitalized patients receiving mechanical ventilation as compared with hospitalized patients breathing room air. Finally, sera from individuals with COVID-19 triggered NET release from control neutrophils in vitro. Future studies should investigate the predictive power of circulating NETs in longitudinal cohorts and determine the extent to which NETs may be novel therapeutic targets in severe COVID-19.


Asunto(s)
Ácidos Nucleicos Libres de Células/metabolismo , Infecciones por Coronavirus/metabolismo , Trampas Extracelulares/metabolismo , Histonas/metabolismo , Neutrófilos/metabolismo , Peroxidasa/metabolismo , Neumonía Viral/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Citrulinación , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/terapia , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Humanos , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pandemias , Recuento de Plaquetas , Neumonía Viral/sangre , Neumonía Viral/terapia , Respiración Artificial , Índice de Severidad de la Enfermedad
8.
Nat Commun ; 11(1): 5838, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: covidwho-933686

RESUMEN

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Modelos Animales de Enfermedad , Neumonía Viral/patología , Neumonía Viral/virología , Factor de Transcripción STAT2/metabolismo , Transducción de Señal , Animales , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Cricetinae , Inmunidad Innata , Interferón Tipo I/genética , Interferón Tipo I/metabolismo , Pulmón/patología , Pulmón/virología , Ratones , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/metabolismo , Factor de Transcripción STAT2/genética , Replicación Viral
9.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artículo en Inglés | MEDLINE | ID: covidwho-927673

RESUMEN

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.


Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Neprilisina/antagonistas & inhibidores , Neumonía Viral/tratamiento farmacológico , Aminobutiratos/administración & dosificación , Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina/administración & dosificación , Animales , Infecciones por Coronavirus/metabolismo , Combinación de Medicamentos , Humanos , Neprilisina/metabolismo , Pandemias , Neumonía Viral/metabolismo , Tetrazoles/administración & dosificación , Tetrazoles/uso terapéutico , Valsartán/administración & dosificación , Valsartán/uso terapéutico
10.
Int J Mol Sci ; 21(22)2020 Nov 16.
Artículo en Inglés | MEDLINE | ID: covidwho-927563

RESUMEN

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread to nearly every continent, registering over 1,250,000 deaths worldwide. The effects of SARS-CoV-2 on host targets remains largely limited, hampering our understanding of Coronavirus Disease 2019 (COVID-19) pathogenesis and the development of therapeutic strategies. The present study used a comprehensive untargeted metabolomic and lipidomic approach to capture the host response to SARS-CoV-2 infection. We found that several circulating lipids acted as potential biomarkers, such as phosphatidylcholine 14:0_22:6 (area under the curve (AUC) = 0.96), phosphatidylcholine 16:1_22:6 (AUC = 0.97), and phosphatidylethanolamine 18:1_20:4 (AUC = 0.94). Furthermore, triglycerides and free fatty acids, especially arachidonic acid (AUC = 0.99) and oleic acid (AUC = 0.98), were well correlated to the severity of the disease. An untargeted analysis of non-critical COVID-19 patients identified a strong alteration of lipids and a perturbation of phenylalanine, tyrosine and tryptophan biosynthesis, phenylalanine metabolism, aminoacyl-tRNA degradation, arachidonic acid metabolism, and the tricarboxylic acid (TCA) cycle. The severity of the disease was characterized by the activation of gluconeogenesis and the metabolism of porphyrins, which play a crucial role in the progress of the infection. In addition, our study provided further evidence for considering phospholipase A2 (PLA2) activity as a potential key factor in the pathogenesis of COVID-19 and a possible therapeutic target. To date, the present study provides the largest untargeted metabolomics and lipidomics analysis of plasma from COVID-19 patients and control groups, identifying new mechanisms associated with the host response to COVID-19, potential plasma biomarkers, and therapeutic targets.


Asunto(s)
Infecciones por Coronavirus/metabolismo , Metaboloma , Neumonía Viral/metabolismo , Anciano , Anciano de 80 o más Años , Aminoácidos/sangre , Ácido Araquidónico/sangre , Biomarcadores/sangre , Ciclo del Ácido Cítrico , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/patología , Femenino , Gluconeogénesis , Humanos , Masculino , Persona de Mediana Edad , Ácido Oléico/sangre , Pandemias , Fosfatidilcolinas/sangre , Fosfatidiletanolaminas/sangre , Fosfolipasas A2/sangre , Neumonía Viral/sangre , Neumonía Viral/patología , Triglicéridos/sangre
11.
Sci Rep ; 10(1): 19395, 2020 11 10.
Artículo en Inglés | MEDLINE | ID: covidwho-919379

RESUMEN

An incomplete understanding of the molecular mechanisms behind impairment of lung pathobiology by COVID-19 complicates its clinical management. In this study, we analyzed the gene expression pattern of cells obtained from biopsies of COVID-19-affected patient and compared to the effects observed in typical SARS-CoV-2 and SARS-CoV-infected cell-lines. We then compared gene expression patterns of COVID-19-affected lung tissues and SARS-CoV-2-infected cell-lines and mapped those to known lung-related molecular networks, including hypoxia induced responses, lung development, respiratory processes, cholesterol biosynthesis and surfactant metabolism; all of which are suspected to be downregulated following SARS-CoV-2 infection based on the observed symptomatic impairments. Network analyses suggest that SARS-CoV-2 infection might lead to acute lung injury in COVID-19 by affecting surfactant proteins and their regulators SPD, SPC, and TTF1 through NSP5 and NSP12; thrombosis regulators PLAT, and EGR1 by ORF8 and NSP12; and mitochondrial NDUFA10, NDUFAF5, and SAMM50 through NSP12. Furthermore, hypoxia response through HIF-1 signaling might also be targeted by SARS-CoV-2 proteins. Drug enrichment analysis of dysregulated genes has allowed us to propose novel therapies, including lung surfactants, respiratory stimulants, sargramostim, and oseltamivir. Our study presents a distinct mechanism of probable virus induced lung damage apart from cytokine storm.


Asunto(s)
Infecciones por Coronavirus/genética , Infecciones por Coronavirus/metabolismo , Perfilación de la Expresión Génica , Pulmón/metabolismo , Terapia Molecular Dirigida , Neumonía Viral/genética , Neumonía Viral/metabolismo , Surfactantes Pulmonares/metabolismo , Biología de Sistemas , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Epigénesis Genética , Humanos , Pulmón/efectos de los fármacos , Especificidad de Órganos , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Proteínas Virales/metabolismo
13.
ACS Chem Neurosci ; 11(22): 3732-3740, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: covidwho-910316

RESUMEN

This Article summarizes the likely benefits of central nervous system oxidative preconditioning in the reduction of COVID-19 based on its putative pathogenesis. The current COVID-19 outbreak caused a pandemic with millions of infected patients and death cases worldwide. The clinical features of severe acute respiratory syndrome coronavirus (SARS-CoV) was initially linked with respiratory disorders, but recent studies have reported alterations of neurological and cerebrovascular functions in COVID-19 patients. The main viral infection features are related to cell death, inflammation, and cytokine generation, which can be associated with the dysregulation of redox systems or oxidative stress. However, until now, there is no available and effective therapeutic approach. Thus, it is necessary to search for care and adequate protection against the disease, especially for susceptible and vulnerable groups. Preconditioning, a well-known antioxidative stress and anti-inflammatory approach, is protective against many neurological age-related disorders. COVID-19 severity and morbidity have been observed in elderly patients. The aim of the present study is to elucidate the possible protective role of oxidative preconditioning in aged patients at high risk of developing severe COVID-19 complications.


Asunto(s)
Betacoronavirus , Encéfalo/irrigación sanguínea , Infecciones por Coronavirus/terapia , Precondicionamiento Isquémico/métodos , Estrés Oxidativo/fisiología , Neumonía Viral/terapia , Betacoronavirus/metabolismo , Encéfalo/metabolismo , Encéfalo/virología , Infecciones por Coronavirus/metabolismo , Humanos , Precondicionamiento Isquémico/tendencias , Pandemias , Neumonía Viral/metabolismo
14.
ACS Chem Neurosci ; 11(22): 3704-3706, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: covidwho-910291

RESUMEN

Postinfection complications of coronavirus disease 2019 (COVID-19) are still unknown, and one of the long-term concerns in infected people are brain pathologies. The question is that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be an environmental factor in accelerating the sporadic neurodegeneration in the infected population. In this regard, induction of protein aggregation in the brain by SARS-CoV-2 intact structure or a peptide derived from spike protein subunits needs to be considered in futures studies. In this paper, we discuss these possibilities using pieces of evidence from other viruses.


Asunto(s)
Betacoronavirus/metabolismo , Encéfalo/metabolismo , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/metabolismo , Neumonía Viral/complicaciones , Neumonía Viral/metabolismo , Agregado de Proteínas/fisiología , Encéfalo/patología , Encéfalo/virología , Infecciones por Coronavirus/patología , Humanos , Pandemias , Neumonía Viral/patología , Factores de Tiempo
15.
Int J Mol Sci ; 21(21)2020 Nov 04.
Artículo en Inglés | MEDLINE | ID: covidwho-909306

RESUMEN

Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus-host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein-protein interfaces responsible for virus entry and infection transmission.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/virología , Interacciones Microbiota-Huesped , Humanos , Pandemias , Neumonía Viral/enzimología , Neumonía Viral/virología , Unión Proteica , Dominios Proteicos , Receptores Virales/metabolismo , Transducción de Señal , Internalización del Virus
17.
Viruses ; 12(10)2020 09 29.
Artículo en Inglés | MEDLINE | ID: covidwho-904976

RESUMEN

Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is responsible for the current global coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The viral entry of SARS-CoV-2 depends on an interaction between the receptor-binding domain of its trimeric spike glycoprotein and the human angiotensin-converting enzyme 2 (ACE2) receptor. A better understanding of the spike/ACE2 interaction is still required to design anti-SARS-CoV-2 therapeutics. Here, we investigated the degree of cooperativity of ACE2 within both the SARS-CoV-2 and the closely related SARS-CoV-1 membrane-bound S glycoproteins. We show that there exist differential inter-protomer conformational transitions between both spike trimers. Interestingly, the SARS-CoV-2 spike exhibits a positive cooperativity for monomeric soluble ACE2 binding when compared to the SARS-CoV-1 spike, which might have more structural restraints. Our findings can be of importance in the development of therapeutics that block the spike/ACE2 interaction.


Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/metabolismo , Virus del SRAS/fisiología , Síndrome Respiratorio Agudo Grave/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Betacoronavirus/metabolismo , Proteínas Portadoras , Infecciones por Coronavirus/virología , Microscopía por Crioelectrón , Células HEK293 , Humanos , Pandemias , Neumonía Viral/virología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Virus del SRAS/metabolismo , Síndrome Respiratorio Agudo Grave/virología , Internalización del Virus
19.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Artículo en Inglés | MEDLINE | ID: covidwho-899862

RESUMEN

Cell entry, the fundamental step in cross-species transmission of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), is initiated by the recognition of the host cell angiotensin-converting enzyme-2 (ACE2) receptor by the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2. To date, several peptides have been proposed against SARS-CoV-2 both as inhibitor agents or as detection tools that can also be attached to the surfaces of nanoparticle carriers. But owing to their natural amino acid sequences, such peptides cannot be considered as efficient therapeutic candidates from a biostability point of view. This discussion demonstrates the design strategy of synthetic nonprotein amino acid substituted peptides with enhanced biostability and binding affinity, the implication of which can make those peptides potential therapeutic agents for inhibition and simple detection tools.


Asunto(s)
Antivirales/uso terapéutico , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Diseño de Fármacos , Fragmentos de Péptidos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Secuencia de Aminoácidos , Antivirales/metabolismo , Betacoronavirus/efectos de los fármacos , Betacoronavirus/genética , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/metabolismo , Humanos , Pandemias , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Neumonía Viral/genética , Neumonía Viral/metabolismo , Unión Proteica/fisiología , Análisis de Secuencia de Proteína/métodos
20.
Sci Rep ; 10(1): 18689, 2020 10 29.
Artículo en Inglés | MEDLINE | ID: covidwho-894418

RESUMEN

The COVID-19 fatality rate is high when compared to the H1N1pdm09 (pandemic Influenza A virus H1N1 subtype) rate, and although both cause an aggravated inflammatory response, the differences in the mechanisms of both pandemic pneumonias need clarification. Thus, our goal was to analyze tissue expression of interleukins 4, 13, (IL-4, IL-13), transforming growth factor-beta (TGF-ß), and the number of M2 macrophages (Sphingosine-1) in patients who died by COVID-19, comparing with cases of severe pneumopathy caused by H1N1pdm09, and a control group without lung injury. Six lung biopsy samples of patients who died of SARS-CoV-2 (COVID-19 group) were used and compared with ten lung samples of adults who died from a severe infection of H1N1pdm09 (H1N1 group) and eleven samples of patients who died from different causes without lung injury (CONTROL group). The expression of IL-4, IL-13, TGF-ß, and M2 macrophages score (Sphingosine-1) were identified through immunohistochemistry (IHC). Significantly higher IL-4 tissue expression and Sphingosine-1 in M2 macrophages were observed in the COVID-19 group compared to both the H1N1 and the CONTROL groups. A different mechanism of diffuse alveolar damage (DAD) in SARS-CoV-2 compared to H1N1pdm09 infections were observed. IL-4 expression and lung remodeling are phenomena observed in both SARS-CoV-2 and H1N1pdm09. However, SARS-CoV-2 seems to promote lung damage through different mechanisms, such as the scarce participation Th1/Th17 response and the higher participation of the Th2. Understanding and managing the aggravated and ineffective immune response elicited by SARS-CoV-2 merits further clarification to improve treatments propose.


Asunto(s)
Infecciones por Coronavirus/metabolismo , Interleucina-13/metabolismo , Interleucina-4/metabolismo , Pulmón/metabolismo , Neumonía Viral/metabolismo , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Infecciones por Coronavirus/patología , Femenino , Humanos , Interleucina-13/genética , Interleucina-4/genética , Pulmón/patología , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , Esfingosina/metabolismo , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/metabolismo
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