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1.
Genes (Basel) ; 11(9)2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32867305

RESUMO

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


Assuntos
Basigina/genética , Infecções por Coronavirus/genética , Furina/genética , Mutação , Pneumonia Viral/genética , Serina Endopeptidases/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Infecções por Coronavirus/patologia , Dipeptidil Peptidase 4/genética , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Polimorfismo de Nucleotídeo Único
2.
J Genet ; 992020.
Artigo em Inglês | MEDLINE | ID: mdl-32661206

RESUMO

At present, more than 200 countries and territories are directly affected by the coronavirus disease-19 (COVID-19) pandemic. Incidence and case fatality rate are significantly higher among elderly individuals (age>60 years), type 2 diabetes and hypertension patients. Cellular receptor ACE2, serine protease TMPRSS2 and exopeptidase CD26 (also known as DPP4) are the three membrane bound proteins potentially implicated in SARS-CoV-2 infection. We hypothesised that common variants from TMPRSS2 and CD26 may play critical role in infection susceptibility of predisposed population or group of individuals. Coding (missense) and regulatory variants from TMPRSS2 and CD26 were studied across 26 global populations. Two missense and five regulatory SNPs were identified to have differential allelic frequency. Significant linkage disequilibrium (LD) signature was observed in different populations. Modelled protein-protein interaction (PPI) predicted strong molecular interaction between these two receptors and SARS-CoV-2 spike protein (S1 domain). However, two missense SNPs, rs12329760 (TMPRSS2) and rs1129599 (CD26), were not found to be involved physically in the said interaction. Four regulatory variants (rs112657409, rs11910678, rs77675406 and rs713400) from TMPRSS2 were found to influence the expression of TMPRSS2 and pathologically relevant MX1. rs13015258 a 50 UTR variant from CD26 have significant role in regulation of expression of key regulatory genes that could be involved in SARS-CoV-2 internalization. Overexpression of CD26 through epigenetic modification at rs13015258-C allele was found critical and could explain the higher SARS-CoV-2 infected fatality rate among type 2 diabetes.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/genética , Dipeptidil Peptidase 4/genética , Pneumonia Viral/genética , Serina Endopeptidases/genética , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/metabolismo , Epigenômica , Predisposição Genética para Doença , Variação Genética , Humanos , Desequilíbrio de Ligação , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Polimorfismo de Nucleotídeo Único , Domínios e Motivos de Interação entre Proteínas , Serina Endopeptidases/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Internalização do Vírus
3.
Molecules ; 25(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: covidwho-436971

RESUMO

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.


Assuntos
Anticoagulantes/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sequência de Aminoácidos , Anticoagulantes/farmacologia , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/enzimologia , Betacoronavirus/genética , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fator Xa/química , Fator Xa/genética , Fator Xa/metabolismo , Hepacivirus/química , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia Estrutural de Proteína , Especificidade por Substrato , Termodinâmica , Trombina/antagonistas & inibidores , Trombina/química , Trombina/genética , Trombina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
6.
Intern Emerg Med ; 15(5): 779-782, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32592113

RESUMO

Patients with diabetes mellitus have been reported to be at a high risk of complications from SARS-CoV2 virus infection (COVID-19). In type 2 diabetes, there is a change in immune system cells, which shift from an anti-inflammatory to a predominantly pro-inflammatory pattern. This altered immune profile may induce important clinical consequences, including increased susceptibility to lung infections; and enhanced local inflammatory response. Furthermore, dipeptidyl peptidase 4 (DPP4) enzyme is highly expressed in the lung, and that it may have additional actions besides its effects on glucose metabolism, which might exert profound pro-inflammatory effects. We briefly review the impact on the inflammatory system of DPP4 for its possible detrimental effect on COVID-19 syndrome, and of DPP4 inhibitors (gliptins), currently used as glucose lowering agents, which may have the potential to exert positive pleiotropic effect on inflammatory diseases, in addition to their effects on glucose metabolism. Thanks to these ancillary effects, gliptins could potentially be "repurposed" as salutary drugs against COVID-19 syndrome, even in non-diabetic subjects. Clinical studies should be designed to investigate this possibility.


Assuntos
Infecções por Coronavirus/imunologia , Diabetes Mellitus/imunologia , Incretinas/imunologia , Pneumonia Viral/imunologia , Animais , Betacoronavirus/imunologia , Dipeptidil Peptidase 4/imunologia , Humanos , Inflamação/imunologia , Pandemias , Prognóstico
8.
J Endocrinol Invest ; 43(8): 1053-1060, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32495299

RESUMO

BACKGROUND: The Coronavirus disease 2019 (COVID-19) and type 2 diabetes (T2D) are two pandemics that share the dramatic impact on global mortality and economic resources. COVID-19 largely exhibits mild to moderate clinical manifestations. However, severe pneumonia with high fatality rate may occur, especially in the elderly and in patients with underlying conditions, such as diabetes and cardiovascular disease. SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) binds to the angiotensin-converting enzyme 2 (ACE2), a ubiquitous trans-membrane carboxypeptidase, to enter the cells. AIMS: This short review discusses some open questions about the link between COVID-19 and diabetes, principally focusing on the possible effects of commonly used drugs in patients with diabetes. RESULTS: Preclinical studies have reported that angiotensin receptor blockers (ARBs) and ACE inhibitors might increase ACE2 expression in several cell types. Hence, it has been speculated that the treatment with these agents might influence the course of the infection, and both harmful and beneficial effects have been supposed. Other pharmacological agents are thought to increase ACE2 expression, including statins and proliferator-activated receptor gamma (PPAR-γ) agonists. All these drug classes are broadly adopted in T2D. Besides ACE2, other unknown co-factors might be involved in cell infection. It has been recently observed that dipeptidyl peptidase-4 (DPP4), the receptor for MERS-CoV (Middle East respiratory syndrome-related coronavirus) and ACE2 have similar expression profiles in the lung. DPP4 has important metabolic and immune functions and is a target for commonly used therapies in T2D. CONCLUSIONS: Although clinical data supporting an influence of all these drugs on the course of the disease are limited, this is an interesting background for further research that might help unravel the complex mechanisms underlying the link between COVID-19 and diabetes.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/metabolismo , Hipoglicemiantes/efeitos adversos , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Antagonistas de Receptores de Angiotensina/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Animais , Infecções por Coronavirus/induzido quimicamente , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Humanos , Pandemias , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/induzido quimicamente
9.
Acta Diabetol ; 57(7): 779-783, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32506195

RESUMO

AIMS: SARS-CoV-2 causes severe respiratory syndrome (COVID-19) with high mortality due to a direct cytotoxic viral effect and a severe systemic inflammation. We are herein discussing a possible novel therapeutic tool for COVID-19. METHODS: Virus binds to the cell surface receptor ACE2; indeed, recent evidences suggested that SARS-CoV-2 may be using as co-receptor, when entering the cells, the same one used by MERS-Co-V, namely the DPP4/CD26 receptor. The aforementioned observation underlined that mechanism of cell entry is supposedly similar among different coronavirus, that the co-expression of ACE2 and DPP4/CD26 could identify those cells targeted by different human coronaviruses and that clinical complications may be similar. RESULTS: The DPP4 family/system was implicated in various physiological processes and diseases of the immune system, and DPP4/CD26 is variously expressed on epithelia and endothelia of the systemic vasculature, lung, kidney, small intestine and heart. In particular, DPP4 distribution in the human respiratory tract may facilitate the entrance of the virus into the airway tract itself and could contribute to the development of cytokine storm and immunopathology in causing fatal COVID-19 pneumonia. CONCLUSIONS: The use of DPP4 inhibitors, such as gliptins, in patients with COVID-19 with, or even without, type 2 diabetes, may offer a simple way to reduce the virus entry and replication into the airways and to hamper the sustained cytokine storm and inflammation within the lung in patients diagnosed with COVID-19 infection.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Pulmão/metabolismo , Pneumonia Viral/tratamento farmacológico , Infecções por Coronavirus/enzimologia , Dipeptidil Peptidase 4/efeitos dos fármacos , Humanos , Pandemias , Pneumonia Viral/enzimologia
10.
EBioMedicine ; 56: 102799, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32474399

RESUMO

A new strain of human coronaviruses (hCoVs), Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has been identified to be responsible for the current outbreak of the coronavirus disease 2019 (COVID-19). Though major symptoms are primarily generated from the respiratory system, neurological symptoms are being reported in some of the confirmed cases, raising concerns of its potential for intracranial invasion and neurological manifestations, both in the acute phase and in the long-term. At present, it remains unclear the extent to which SARS-CoV-2 is present in the brain, and if so, its pathogenic role in the central nervous system (CNS). Evidence for neuroinvasion and neurovirulence of hCoVs has been recognised in animal and human studies. Given that SARS-CoV-2 belongs to the same family and shares characteristics in terms of receptor binding properties, it is worthwhile exploring its potential CNS manifestations. This review summarises previous findings from hCoVs in relation to the CNS, and compares these with the new strain, aiming to provide a better understanding of the effects of SARS-CoV-2 on the CNS.


Assuntos
Betacoronavirus/fisiologia , Encéfalo/virologia , Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Animais , Betacoronavirus/isolamento & purificação , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/virologia , Infecções por Coronavirus/virologia , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/metabolismo , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio/isolamento & purificação , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Pandemias , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/virologia , Proteínas Virais/química , Proteínas Virais/metabolismo
11.
Molecules ; 25(11)2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32485894

RESUMO

The coronavirus disease, COVID-19, caused by the novel coronavirus SARS-CoV-2, which first emerged in Wuhan, China and was made known to the World in December 2019 turned into a pandemic causing more than 126,124 deaths worldwide up to April 16th, 2020. It has 79.5% sequence identity with SARS-CoV-1 and the same strategy for host cell invasion through the ACE-2 surface protein. Since the development of novel drugs is a long-lasting process, researchers look for effective substances among drugs already approved or developed for other purposes. The 3D structure of the SARS-CoV-2 main protease was compared with the 3D structures of seven proteases, which are drug targets, and docking analysis to the SARS-CoV-2 protease structure of thirty four approved and on-trial protease inhibitors was performed. Increased 3D structural similarity between the SARS-CoV-2 main protease, the HCV protease and α-thrombin was found. According to docking analysis the most promising results were found for HCV protease, DPP-4, α-thrombin and coagulation Factor Xa known inhibitors, with several of them exhibiting estimated free binding energy lower than -8.00 kcal/mol and better prediction results than reference compounds. Since some of the compounds are well-tolerated drugs, the promising in silico results may warrant further evaluation for viral anticipation. DPP-4 inhibitors with anti-viral action may be more useful for infected patients with diabetes, while anti-coagulant treatment is proposed in severe SARS-CoV-2 induced pneumonia.


Assuntos
Anticoagulantes/química , Antivirais/química , Betacoronavirus/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/química , Inibidores de Proteases/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Sequência de Aminoácidos , Anticoagulantes/farmacologia , Antivirais/farmacologia , Betacoronavirus/química , Betacoronavirus/enzimologia , Betacoronavirus/genética , Sítios de Ligação , Infecções por Coronavirus/tratamento farmacológico , Cisteína Endopeptidases/química , Cisteína Endopeptidases/genética , Cisteína Endopeptidases/metabolismo , Dipeptidil Peptidase 4/química , Dipeptidil Peptidase 4/genética , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fator Xa/química , Fator Xa/genética , Fator Xa/metabolismo , Hepacivirus/química , Hepacivirus/enzimologia , Hepacivirus/genética , Humanos , Simulação de Acoplamento Molecular , Pandemias , Pneumonia Viral/tratamento farmacológico , Inibidores de Proteases/farmacologia , Ligação Proteica , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Alinhamento de Sequência , Homologia Estrutural de Proteína , Especificidade por Substrato , Termodinâmica , Trombina/antagonistas & inibidores , Trombina/química , Trombina/genética , Trombina/metabolismo , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
12.
Rev Neurosci ; 31(4): 453-456, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: covidwho-401430

RESUMO

Coronaviruses disease (COVID-19) has caused major outbreaks. A novel variant, SARS-CoV-2, is responsible for COVID-19 pandemic. Clinical presentations and pathological mechanisms of COVID-19 are broad. The respiratory aspect of the disease has been extensively researched. Emerging studies point out the possibility of the central nervous system (CNS) involvement by COVID-19. Here, we discuss the current evidence for CNS involvement in COVID-19 and highlight that the high pathogenicity of SARS-CoV-2 might be due to its neuroinvasive potential.


Assuntos
Viroses do Sistema Nervoso Central/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Síndrome Respiratória Aguda Grave/fisiopatologia , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Barreira Hematoencefálica , Tronco Encefálico , Dipeptidil Peptidase 4/metabolismo , Osso Etmoide , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio , Mucosa Olfatória , Pandemias , Peptidil Dipeptidase A/metabolismo , Vírus da SARS , Tálamo , Tropismo Viral , Internalização do Vírus
13.
PLoS One ; 15(5): e0232757, 2020.
Artigo em Inglês | MEDLINE | ID: covidwho-209798

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infection and continues to infect humans, thereby contributing to a high mortality rate (34.3% in 2019). In the absence of an available licensed vaccine and antiviral agent, therapeutic human antibodies have been suggested as candidates for treatment. In this study, human monoclonal antibodies were isolated by sorting B cells from patient's PBMC cells with prefusion stabilized spike (S) probes and a direct immunoglobulin cloning strategy. We identified six receptor-binding domain (RBD)-specific and five S1 (non-RBD)-specific antibodies, among which, only the RBD-specific antibodies showed high neutralizing potency (IC50 0.006-1.787 µg/ml) as well as high affinity to RBD. Notably, passive immunization using a highly potent antibody (KNIH90-F1) at a relatively low dose (2 mg/kg) completely protected transgenic mice expressing human DPP4 against MERS-CoV lethal challenge. These results suggested that human monoclonal antibodies isolated by using the rationally designed prefusion MERS-CoV S probe could be considered potential candidates for the development of therapeutic and/or prophylactic antiviral agents for MERS-CoV human infection.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Linhagem Celular , Chlorocebus aethiops , Dipeptidil Peptidase 4/genética , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , República da Coreia , Células Vero
14.
PLoS One ; 15(5): e0232757, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32384116

RESUMO

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory infection and continues to infect humans, thereby contributing to a high mortality rate (34.3% in 2019). In the absence of an available licensed vaccine and antiviral agent, therapeutic human antibodies have been suggested as candidates for treatment. In this study, human monoclonal antibodies were isolated by sorting B cells from patient's PBMC cells with prefusion stabilized spike (S) probes and a direct immunoglobulin cloning strategy. We identified six receptor-binding domain (RBD)-specific and five S1 (non-RBD)-specific antibodies, among which, only the RBD-specific antibodies showed high neutralizing potency (IC50 0.006-1.787 µg/ml) as well as high affinity to RBD. Notably, passive immunization using a highly potent antibody (KNIH90-F1) at a relatively low dose (2 mg/kg) completely protected transgenic mice expressing human DPP4 against MERS-CoV lethal challenge. These results suggested that human monoclonal antibodies isolated by using the rationally designed prefusion MERS-CoV S probe could be considered potential candidates for the development of therapeutic and/or prophylactic antiviral agents for MERS-CoV human infection.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/farmacologia , Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Linhagem Celular , Chlorocebus aethiops , Dipeptidil Peptidase 4/genética , Humanos , Leucócitos Mononucleares/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , República da Coreia , Células Vero
16.
Rev Neurosci ; 31(4): 453-456, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32463395

RESUMO

Coronaviruses disease (COVID-19) has caused major outbreaks. A novel variant, SARS-CoV-2, is responsible for COVID-19 pandemic. Clinical presentations and pathological mechanisms of COVID-19 are broad. The respiratory aspect of the disease has been extensively researched. Emerging studies point out the possibility of the central nervous system (CNS) involvement by COVID-19. Here, we discuss the current evidence for CNS involvement in COVID-19 and highlight that the high pathogenicity of SARS-CoV-2 might be due to its neuroinvasive potential.


Assuntos
Viroses do Sistema Nervoso Central/fisiopatologia , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/fisiopatologia , Síndrome Respiratória Aguda Grave/fisiopatologia , Betacoronavirus/metabolismo , Betacoronavirus/fisiologia , Barreira Hematoencefálica , Tronco Encefálico , Dipeptidil Peptidase 4/metabolismo , Osso Etmoide , Humanos , Coronavírus da Síndrome Respiratória do Oriente Médio , Mucosa Olfatória , Pandemias , Peptidil Dipeptidase A/metabolismo , Vírus da SARS , Tálamo , Tropismo Viral , Internalização do Vírus
17.
J Diabetes ; 12(9): 649-658, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32394639

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic is caused by a novel betacoronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome (MERS-CoV), which cause acute respiratory distress syndrome and case fatalities. COVID-19 disease severity is worse in older obese patients with comorbidities such as diabetes, hypertension, cardiovascular disease, and chronic lung disease. Cell binding and entry of betacoronaviruses is via their surface spike glycoprotein; SARS-CoV binds to the metalloprotease angiotensin-converting enzyme 2 (ACE2), MERS-CoV utilizes dipeptidyl peptidase 4 (DPP4), and recent modeling of the structure of SARS-CoV-2 spike glycoprotein predicts that it can interact with human DPP4 in addition to ACE2. DPP4 is a ubiquitous membrane-bound aminopeptidase that circulates in plasma; it is multifunctional with roles in nutrition, metabolism, and immune and endocrine systems. DPP4 activity differentially regulates glucose homeostasis and inflammation via its enzymatic activity and nonenzymatic immunomodulatory effects. The importance of DPP4 for the medical community has been highlighted by the approval of DPP4 inhibitors, or gliptins, for the treatment of type 2 diabetes mellitus. This review discusses the dysregulation of DPP4 in COVID-19 comorbid conditions; DPP4 activity is higher in older individuals and increased plasma DPP4 is a predictor of the onset of metabolic syndrome. DPP4 upregulation may be a determinant of COVID-19 disease severity, which creates interest regarding the use of gliptins in management of COVID-19. Also, knowledge of the chemistry and biology of DPP4 could be utilized to develop novel therapies to block viral entry of some betacoronaviruses, potentially including SARS-CoV-2.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Comorbidade , Dipeptidil Peptidase 4 , Humanos , Pandemias
19.
Diabetes Res Clin Pract ; 163: 108162, 2020 May.
Artigo em Inglês | MEDLINE | ID: covidwho-127824

RESUMO

Diabetes could be a risk factor for severity and mortality in patients with coronavirus disease 2019 COVID-19. It has been hypothesized that DPP4 inhibition, a therapy currently available for type 2 diabetes, might represent a target for decreasing the risk of the acute respiratory complications of the COVID-19 infection but (1) lack of demonstration of SARS-CoV2 binding to DPP4 (2) possible protective role of sDPP4 in Middle East respiratory Syndrome (MERS-CoV) (3) demonstrated inhibition and downregulation of DPP4 by HIV1 and MERS-CoV and (4) not exclusive role of the receptor binding in tropism of the Coronavirus family, support that DPP4 inhibition at present doesn't represent a plausible approach to mitigate COVID-19.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/farmacologia , Humanos , Hipoglicemiantes/farmacologia , Pandemias
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