RESUMEN
A new coronavirus, known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is the aetiological agent responsible for the 2019-2020 viral pneumonia outbreak of coronavirus disease 2019 (COVID-19)1-4. Currently, there are no targeted therapeutic agents for the treatment of this disease, and effective treatment options remain very limited. Here we describe the results of a programme that aimed to rapidly discover lead compounds for clinical use, by combining structure-assisted drug design, virtual drug screening and high-throughput screening. This programme focused on identifying drug leads that target main protease (Mpro) of SARS-CoV-2: Mpro is a key enzyme of coronaviruses and has a pivotal role in mediating viral replication and transcription, making it an attractive drug target for SARS-CoV-25,6. We identified a mechanism-based inhibitor (N3) by computer-aided drug design, and then determined the crystal structure of Mpro of SARS-CoV-2 in complex with this compound. Through a combination of structure-based virtual and high-throughput screening, we assayed more than 10,000 compounds-including approved drugs, drug candidates in clinical trials and other pharmacologically active compounds-as inhibitors of Mpro. Six of these compounds inhibited Mpro, showing half-maximal inhibitory concentration values that ranged from 0.67 to 21.4 µM. One of these compounds (ebselen) also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of our screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases for which no specific drugs or vaccines are available.
Asunto(s)
Betacoronavirus/química , Cisteína Endopeptidasas/química , Descubrimiento de Drogas/métodos , Modelos Moleculares , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Proteínas no Estructurales Virales/química , Antivirales/química , Antivirales/farmacología , Betacoronavirus/efectos de los fármacos , COVID-19 , Células Cultivadas/virología , Proteasas 3C de Coronavirus , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/virología , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Pandemias , Neumonía Viral/enzimología , Neumonía Viral/virología , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , SARS-CoV-2RESUMEN
Coronavirus disease 2019 (COVID-19) is a global pandemic affecting 185 countries and >3 000 000 patients worldwide as of April 28, 2020. COVID-19 is caused by severe acute respiratory syndrome coronavirus 2, which invades cells through the angiotensin-converting enzyme 2 receptor. Among patients with COVID-19, there is a high prevalence of cardiovascular disease, and >7% of patients experience myocardial injury from the infection (22% of critically ill patients). Although angiotensin-converting enzyme 2 serves as the portal for infection, the role of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers requires further investigation. COVID-19 poses a challenge for heart transplantation, affecting donor selection, immunosuppression, and posttransplant management. There are a number of promising therapies under active investigation to treat and prevent COVID-19.
Asunto(s)
Betacoronavirus , Enfermedades Cardiovasculares , Infecciones por Coronavirus , Pandemias , Peptidil-Dipeptidasa A , Neumonía Viral , Antagonistas de Receptores de Angiotensina/uso terapéutico , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , COVID-19 , Enfermedades Cardiovasculares/complicaciones , Enfermedades Cardiovasculares/enzimología , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Humanos , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/complicaciones , Neumonía Viral/enzimología , Neumonía Viral/terapia , Neumonía Viral/virología , Receptores Virales/antagonistas & inhibidores , Receptores Virales/metabolismo , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
MOTIVATION: Since December 2019, the newly identified coronavirus SARS-CoV-2 has caused a massive health crisis worldwide and resulted in over 70 000 COVID-19 infections so far. Clinical drugs targeting SARS-CoV-2 are urgently needed to decrease the high fatality rate of confirmed COVID-19 patients. Traditional de novo drug discovery needs more than 10 years, so drug repurposing seems the best option currently to find potential drugs for treating COVID-19. RESULTS: Compared with traditional non-covalent drugs, covalent drugs have attracted escalating attention recent years due to their advantages in potential specificity upon careful design, efficiency and patient burden. We recently developed a computational protocol named as SCAR (steric-clashes alleviating receptors) for discovering covalent drugs. In this work, we used the SCAR protocol to identify possible covalent drugs (approved or clinically tested) targeting the main protease (3CLpro) of SARS-CoV-2. We identified 11 potential hits, among which at least six hits were exclusively enriched by the SCAR protocol. Since the preclinical or clinical information of these identified drugs is already available, they might be ready for being clinically tested in the treatment of COVID-19. CONTACT: senliu.ctgu@gmail.com.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus , Coronavirus , Cisteína Endopeptidasas , Sistemas de Liberación de Medicamentos , Pandemias , Neumonía Viral , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo , Proteínas no Estructurales Virales , Betacoronavirus/efectos de los fármacos , COVID-19 , Proteasas 3C de Coronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/enzimología , Cisteína Endopeptidasas/efectos de los fármacos , Humanos , Péptido Hidrolasas/efectos de los fármacos , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/enzimología , SARS-CoV-2 , Proteínas no Estructurales Virales/efectos de los fármacosRESUMEN
Infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to coronavirus disease 2019 (COVID-19), which poses an unprecedented worldwide health crisis, and has been declared a pandemic by the World Health Organization (WHO) on March 11, 2020. The angiotensin converting enzyme 2 (ACE2) has been suggested to be the key protein used by SARS-CoV-2 for host cell entry. In their recent work, Lindskog and colleagues (Hikmet et al, 2020) report that ACE2 is expressed at very low protein levels-if at all-in respiratory epithelial cells. Severe COVID-19, however, is characterized by acute respiratory distress syndrome and extensive damage to the alveoli in the lung parenchyma. Then, what is the role of the airway epithelium in the early stages of COVID-19, and which cells need to be studied to characterize the biological mechanisms responsible for the progression to severe disease after initial infection by the novel coronavirus?
Asunto(s)
Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/metabolismo , Neumonía Viral/virología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/virología , Síndrome Respiratorio Agudo Grave/metabolismo , Síndrome Respiratorio Agudo Grave/virología , Enzima Convertidora de Angiotensina 2 , Betacoronavirus , COVID-19 , Conjuntiva/metabolismo , Infecciones por Coronavirus/enzimología , Interacciones Microbiota-Huesped/genética , Humanos , Especificidad de Órganos , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/enzimología , SARS-CoV-2 , Síndrome Respiratorio Agudo Grave/enzimología , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Human angiotensin-converting enzyme 2 (ACE2) facilitates cellular entry of severe acute respiratory syndrome coronavirus (SARS-CoV) and SARS-CoV-2 as their common receptor. During infection, ACE2-expressing tissues become direct targets, resulting in serious pathological changes and progressive multiple organ failure or even death in severe cases. However, as an essential component of renin-angiotensin system (RAS), ACE2 confers protective effects in physiological circumstance, including maintaining cardiovascular homeostasis, fluid, and electrolyte balance. The absence of protective role of ACE2 leads to dysregulated RAS and thus acute changes under multiple pathological scenarios including SARS. This potentially shared mechanism may also be the molecular explanation for pathogenesis driven by SARS-CoV-2. We reasonably speculate several potential directions of clinical management including host-directed therapies aiming to restore dysregulated RAS caused by ACE2 deficiency. Enriched knowledge of ACE2 learned from SARS and COVID-19 outbreaks can provide, despite their inherent tragedy, informative clues for emerging pandemic preparedness.
Asunto(s)
Betacoronavirus/fisiología , Infecciones por Coronavirus/enzimología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/enzimología , Síndrome Respiratorio Agudo Grave/enzimología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/fisiología , Internalización del Virus , Enzima Convertidora de Angiotensina 2 , COVID-19 , Sistemas de Liberación de Medicamentos , Humanos , Pandemias , Peptidil-Dipeptidasa A/deficiencia , SARS-CoV-2RESUMEN
Patients who died from COVID-19 often had comorbidities, such as hypertension, diabetes, and chronic obstructive lung disease. Although angiotensin-converting enzyme 2 (ACE2) is crucial for SARS-CoV-2 to bind and enter host cells, no study has systematically assessed the ACE2 expression in the lungs of patients with these diseases. Here, we analyzed over 700 lung transcriptome samples from patients with comorbidities associated with severe COVID-19 and found that ACE2 was highly expressed in these patients compared to control individuals. This finding suggests that patients with such comorbidities may have higher chances of developing severe COVID-19. Correlation and network analyses revealed many potential regulators of ACE2 in the human lung, including genes related to histone modifications, such as HAT1, HDAC2, and KDM5B. Our systems biology approach offers a possible explanation for increased COVID-19 severity in patients with certain comorbidities.
Asunto(s)
Infecciones por Coronavirus/epidemiología , Pulmón/enzimología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/epidemiología , Enzima Convertidora de Angiotensina 2 , COVID-19 , Estudios de Casos y Controles , Trastornos Cerebrovasculares/epidemiología , Trastornos Cerebrovasculares/genética , Comorbilidad , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/genética , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/genética , Complicaciones de la Diabetes/epidemiología , Complicaciones de la Diabetes/genética , Epigenómica , Femenino , Humanos , Hipertensión/epidemiología , Hipertensión/genética , Masculino , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/enzimología , Neumonía Viral/genética , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/genética , Índice de Severidad de la Enfermedad , Biología de Sistemas , TranscriptomaRESUMEN
COVID-19, caused by the SARS-CoV-2 virus, is a major source of morbidity and mortality due to its inflammatory effects in the lungs and heart. The p38 MAPK pathway plays a crucial role in the release of pro-inflammatory cytokines such as IL-6 and has been implicated in acute lung injury and myocardial dysfunction. The overwhelming inflammatory response in COVID-19 infection may be caused by disproportionately upregulated p38 activity, explained by two mechanisms. First, angiotensin-converting enzyme 2 (ACE2) activity is lost during SARS-CoV-2 viral entry. ACE2 is highly expressed in the lungs and heart and converts Angiotensin II into Angiotensin 1-7. Angiotensin II signals proinflammatory, pro-vasoconstrictive, pro-thrombotic activity through p38 MAPK activation, which is countered by Angiotensin 1-7 downregulation of p38 activity. Loss of ACE2 upon viral entry may tip the balance towards destructive p38 signaling through Angiotensin II. Second, SARS-CoV was previously shown to directly upregulate p38 activity via a viral protein, similar to other RNA respiratory viruses that may hijack p38 activity to promote replication. Given the homology between SARS-CoV and SARS-CoV-2, the latter may employ a similar mechanism. Thus, SARS-CoV-2 may induce overwhelming inflammation by directly activating p38 and downregulating a key inhibitory pathway, while simultaneously taking advantage of p38 activity to replicate. Therapeutic inhibition of p38 could therefore attenuate COVID-19 infection. Interestingly, a prior preclinical study showed protective effects of p38 inhibition in a SARS-CoV mouse model. A number of p38 inhibitors are in the clinical stage and should be considered for clinical trials in serious COVID-19 infection.
Asunto(s)
Antivirales/farmacología , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/enzimología , Activación Enzimática , Interacciones Huésped-Patógeno/fisiología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/virología , Pulmón/metabolismo , Pulmón/fisiopatología , Pulmón/virología , Pandemias , Neumonía Viral/enzimología , SARS-CoV-2 , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Tratamiento Farmacológico de COVID-19RESUMEN
PARP1, the major isoform of a family of ADP-ribosylating enzymes, has been implicated in the regulation of various biological processes including DNA repair, gene transcription, and cell death. The concept that PARP1 becomes activated in acute lung injury (ALI) and that pharmacological inhibition or genetic deletion of this enzyme can provide therapeutic benefits emerged over 20 years ago. The current article provides an overview of the cellular mechanisms involved in the pathogenetic roles of PARP1 in ALI and provides an overview of the preclinical data supporting the efficacy of PARP (poly[ADP-ribose] polymerase) inhibitors. In recent years, several ultrapotent PARP inhibitors have been approved for clinical use (for the therapy of various oncological diseases): these newly-approved PARP inhibitors were recently reported to show efficacy in animal models of ALI. These observations offer the possibility of therapeutic repurposing of these inhibitors for patients with ALI. The current article lays out a potential roadmap for such repurposing efforts. In addition, the article also overviews the scientific basis of potentially applying PARP inhibitors for the experimental therapy of viral ALI, such as coronavirus disease (COVID-19)-associated ALI.
Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Infecciones por Coronavirus/tratamiento farmacológico , Pulmón/efectos de los fármacos , Neumonía Viral/tratamiento farmacológico , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Lesión Pulmonar Aguda/enzimología , Lesión Pulmonar Aguda/virología , Animales , Antivirales/efectos adversos , Betacoronavirus/patogenicidad , COVID-19 , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno , Humanos , Pulmón/enzimología , Pulmón/virología , Pandemias , Neumonía Viral/enzimología , Neumonía Viral/virología , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , SARS-CoV-2 , Transducción de Señal/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.
Asunto(s)
Antivirales/farmacología , Infecciones por Coronavirus/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Lopinavir/química , Lopinavir/farmacología , Neumonía Viral/tratamiento farmacológico , Ritonavir/química , Ritonavir/farmacología , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/enzimología , COVID-19 , Dominio Catalítico , Proteasas 3C de Coronavirus , Infecciones por Coronavirus/enzimología , Infecciones por Coronavirus/virología , Cisteína Endopeptidasas/química , Cisteína Endopeptidasas/metabolismo , Reposicionamiento de Medicamentos , Inhibidores Enzimáticos/uso terapéutico , Humanos , Lopinavir/uso terapéutico , Simulación de Dinámica Molecular , Pandemias , Neumonía Viral/enzimología , Neumonía Viral/virología , Unión Proteica , Estructura Terciaria de Proteína , Ritonavir/uso terapéutico , SARS-CoV-2 , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismoRESUMEN
The incidence, severity, and mortality of ongoing coronavirus infectious disease 19 (COVID-19) is greater in men compared with women, but the underlying factors contributing to this sex difference are still being explored. In the current study, using primary isolated human airway smooth muscle (ASM) cells from normal males versus females as a model, we explored the effect of estrogen versus testosterone in modulating the expression of angiotensin converting enzyme 2 (ACE2), a cell entry point for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using confocal imaging, we found that ACE2 is expressed in human ASM. Furthermore, Western analysis of ASM cell lysates showed significantly lower ACE2 expression in females compared with males at baseline. In addition, ASM cells exposed to estrogen and testosterone for 24 h showed that testosterone significantly upregulates ACE2 expression in both males and females, whereas estrogen downregulates ACE2, albeit not significant compared with vehicle. These intrinsic and sex steroids induced differences may help explain sex differences in COVID-19.
Asunto(s)
Infecciones por Coronavirus/metabolismo , Peptidil-Dipeptidasa A/biosíntesis , Neumonía Viral/metabolismo , Sistema Respiratorio/metabolismo , Adulto , Anciano , Enzima Convertidora de Angiotensina 2 , COVID-19 , Células Cultivadas , Infecciones por Coronavirus/enzimología , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/enzimología , Miocitos del Músculo Liso/metabolismo , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/enzimología , Sistema Respiratorio/citología , Sistema Respiratorio/efectos de los fármacos , Sistema Respiratorio/enzimología , Factores Sexuales , Testosterona/metabolismo , Testosterona/farmacologíaRESUMEN
The prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) quickly reached pandemic proportions, and knowledge about this virus and coronavirus disease 2019 (COVID-19) has expanded rapidly. This review focuses primarily on mechanisms that contribute to acute cardiac injury and dysfunction, which are common in patients with severe disease. The etiology of cardiac injury is multifactorial, and the extent is likely enhanced by preexisting cardiovascular disease. Disruption of homeostatic mechanisms secondary to pulmonary pathology ranks high on the list, and there is growing evidence that direct infection of cardiac cells can occur. Angiotensin-converting enzyme 2 (ACE2) plays a central role in COVID-19 and is a necessary receptor for viral entry into human cells. ACE2 normally not only eliminates angiotensin II (Ang II) by converting it to Ang-(1-7) but also elicits a beneficial response profile counteracting that of Ang II. Molecular analyses of single nuclei from human hearts have shown that ACE2 is most highly expressed by pericytes. Given the important roles that pericytes have in the microvasculature, infection of these cells could compromise myocardial supply to meet metabolic demand. Furthermore, ACE2 activity is crucial for opposing adverse effects of locally generated Ang II, so virus-mediated internalization of ACE2 could exacerbate pathology by this mechanism. While the role of cardiac pericytes in acute heart injury by SARS-CoV-2 requires investigation, expression of ACE2 by these cells has broader implications for cardiac pathophysiology.
Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/enzimología , Cardiopatías/enzimología , Peptidil-Dipeptidasa A/metabolismo , Pericitos/enzimología , Neumonía Viral/enzimología , Internalización del Virus , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Infecciones por Coronavirus/virología , Cardiopatías/fisiopatología , Cardiopatías/virología , Interacciones Huésped-Patógeno , Humanos , Pandemias , Pericitos/virología , Neumonía Viral/virología , SARS-CoV-2RESUMEN
The novel SARS coronavirus SARS-CoV-2 pandemic may be particularly deleterious to patients with underlying cardiovascular disease (CVD). The mechanism for SARS-CoV-2 infection is the requisite binding of the virus to the membrane-bound form of angiotensin-converting enzyme 2 (ACE2) and internalization of the complex by the host cell. Recognition that ACE2 is the coreceptor for the coronavirus has prompted new therapeutic approaches to block the enzyme or reduce its expression to prevent the cellular entry and SARS-CoV-2 infection in tissues that express ACE2 including lung, heart, kidney, brain, and gut. ACE2, however, is a key enzymatic component of the renin-angiotensin-aldosterone system (RAAS); ACE2 degrades ANG II, a peptide with multiple actions that promote CVD, and generates Ang-(1-7), which antagonizes the effects of ANG II. Moreover, experimental evidence suggests that RAAS blockade by ACE inhibitors, ANG II type 1 receptor antagonists, and mineralocorticoid antagonists, as well as statins, enhance ACE2 which, in part, contributes to the benefit of these regimens. In lieu of the fact that many older patients with hypertension or other CVDs are routinely treated with RAAS blockers and statins, new clinical concerns have developed regarding whether these patients are at greater risk for SARS-CoV-2 infection, whether RAAS and statin therapy should be discontinued, and the potential consequences of RAAS blockade to COVID-19-related pathologies such as acute and chronic respiratory disease. The current perspective critically examines the evidence for ACE2 regulation by RAAS blockade and statins, the cardiovascular benefits of ACE2, and whether ACE2 blockade is a viable approach to attenuate COVID-19.
Asunto(s)
Betacoronavirus/fisiología , Enfermedades Cardiovasculares/enzimología , Enfermedades Cardiovasculares/virología , Infecciones por Coronavirus/enzimología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/enzimología , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus/metabolismo , COVID-19 , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Humanos , Masculino , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/virología , Ratas , Ratas Endogámicas Lew , SARS-CoV-2 , Internalización del VirusRESUMEN
BACKGROUND: Coronavirus disease 2019 (COVID-19) has infected more than 4 million people within 4 months. There is an urgent need to properly identify high-risk cases that are more likely to deteriorate even if they present mild diseases on admission. METHODS: A multicenter nested case-control study was conducted in four designated hospitals in China enrolling confirmed COVID-19 patients who were mild on admission. Baseline clinical characteristics were compared between patients with stable mild illness (stable mild group) and those who deteriorated from mild to severe illness (progression group). RESULTS: From Jan 17, 2020, to Feb 1, 2020, 85 confirmed COVID-19 patients were enrolled, including 16 in the progression group and 69 in the stable mild group. Compared to stable mild group (n = 69), patients in the progression group (n = 16) were more likely to be older, male, presented with dyspnea, with hypertension, and with higher levels of lactase dehydrogenase and c-reactive protein. In multivariate logistic regression analysis, advanced age (odds ratio [OR], 1.012; 95% confidence interval [CI], 1.020-1.166; P = 0.011) and the higher level of lactase dehydrogenase (OR, 1.012; 95% CI, 1.001-1.024; P = 0.038) were independently associated with exacerbation in mild COVID-19 patients. CONCLUSION: Advanced age and high LDH level are independent risk factors for exacerbation in mild COVID-19 patients. Among the mild patients, clinicians should pay more attention to the elderly patients or those with high LDH levels.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/enzimología , L-Lactato Deshidrogenasa/metabolismo , Neumonía Viral/enzimología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , COVID-19 , Estudios de Casos y Controles , China , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Progresión de la Enfermedad , Susceptibilidad a Enfermedades , Femenino , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Factores de Riesgo , SARS-CoV-2 , Adulto JovenRESUMEN
BACKGROUND: The clinical presentation of European patients with mild-to-moderate COVID-19 infection is still unknown. OBJECTIVE: To study the clinical presentation of COVID-19 in Europe. METHODS: Patients with positive diagnosis of COVID-19 were recruited from 18 European hospitals. Epidemiological and clinical data were obtained through a standardized questionnaire. Bayesian analysis was used for analysing the relationship between outcomes. RESULTS: A total of 1,420 patients completed the study (962 females, 30.7% of healthcare workers). The mean age of patients was 39.17 ± 12.09 years. The most common symptoms were headache (70.3%), loss of smell (70.2%), nasal obstruction (67.8%), cough (63.2%), asthenia (63.3%), myalgia (62.5%), rhinorrhea (60.1%), gustatory dysfunction (54.2%) and sore throat (52.9%). Fever was reported by 45.4%. The mean duration of COVID-19 symptoms of mild-to-moderate cured patients was 11.5 ± 5.7 days. The prevalence of symptoms significantly varied according to age and sex. Young patients more frequently had ear, nose and throat complaints, whereas elderly individuals often presented fever, fatigue and loss of appetite. Loss of smell, headache, nasal obstruction and fatigue were more prevalent in female patients. The loss of smell was a key symptom of mild-to-moderate COVID-19 patients and was not associated with nasal obstruction and rhinorrhea. Loss of smell persisted at least 7 days after the disease in 37.5% of cured patients. CONCLUSION: The clinical presentation of mild-to-moderate COVID-19 substantially varies according to the age and the sex characteristics of patients. Olfactory dysfunction seems to be an important underestimated symptom of mild-to-moderate COVID-19 that needs to be recognized as such by the WHO.
Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/diagnóstico , Cefalea/epidemiología , Trastornos del Olfato/epidemiología , Neumonía Viral/complicaciones , Neumonía Viral/diagnóstico , Trastornos del Gusto/epidemiología , Adulto , Factores de Edad , Teorema de Bayes , COVID-19 , Infecciones por Coronavirus/enzimología , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mialgia/epidemiología , Pandemias , Neumonía Viral/enzimología , Prevalencia , SARS-CoV-2 , Factores Sexuales , Evaluación de SíntomasRESUMEN
It has been reported that SARS-CoV-2 may use ACE2 as a receptor to gain entry into human cells, in a way similar to that of SARS-CoV. Analyzing the distribution and expression level of ACE2 may therefore help reveal underlying mechanisms of viral susceptibility and post-infection modulation. In this study, we utilized previously uploaded information on ACE2 expression in various conditions including SARS-CoA to evaluate the role of ACE2 in SARS-CoV and extrapolate that to COVID-19. We found that the expression of ACE2 in healthy populations and patients with underlying diseases was not significantly different. However, based on the elevated expression of ACE2 in cigarette smokers, we speculate that long-term smoking may be a risk factor for COVID-19. Analysis of ACE2 in SARS-CoV infected cells suggests that ACE2 is not only a receptor but is also involved in post-infection regulation, including immune response, cytokine secretion, and viral genome replication. Moreover, we constructed Protein-protein interaction (PPI) networks and identified hub genes in viral activity and cytokine secretion. Our findings may help clinicians and researchers gain more insight into the pathogenesis of SARS-CoV-2 and design therapeutic strategies for COVID-19.
Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/enzimología , Regulación Enzimológica de la Expresión Génica , Pulmón/enzimología , Peptidil-Dipeptidasa A/biosíntesis , Neumonía Viral/enzimología , Fumar/efectos adversos , Enzima Convertidora de Angiotensina 2 , COVID-19 , Infecciones por Coronavirus/patología , Humanos , Pandemias , Neumonía Viral/patología , Mapas de Interacción de Proteínas , SARS-CoV-2RESUMEN
Patients with COVID-19 who require ICU admission might have the cytokine storm. It is a state of out-of-control release of a variety of inflammatory cytokines. The molecular mechanism of the cytokine storm has not been explored extensively yet. The attachment of SARS-CoV-2 spike glycoprotein with angiotensin-converting enzyme 2 (ACE2), as its cellular receptor, triggers complex molecular events that leads to hyperinflammation. Four molecular axes that may be involved in SARS-CoV-2 driven inflammatory cytokine overproduction are addressed in this work. The virus-mediated down-regulation of ACE2 causes a burst of inflammatory cytokine release through dysregulation of the renin-angiotensin-aldosterone system (ACE/angiotensin II/AT1R axis), attenuation of Mas receptor (ACE2/MasR axis), increased activation of [des-Arg9]-bradykinin (ACE2/bradykinin B1R/DABK axis), and activation of the complement system including C5a and C5b-9 components. The molecular clarification of these axes will elucidate an array of therapeutic strategies to confront the cytokine storm in order to prevent and treat COVID-19 associated acute respiratory distress syndrome.
Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/metabolismo , Citocinas/metabolismo , Inflamación/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/inmunología , Neumonía Viral/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Enzima Convertidora de Angiotensina 2 , Betacoronavirus/patogenicidad , Bradiquinina/metabolismo , COVID-19 , Complemento C5a/inmunología , Complemento C5a/metabolismo , Complemento C5b/inmunología , Complemento C5b/metabolismo , Infecciones por Coronavirus/enzimología , Humanos , Inflamación/enzimología , Inflamación/inmunología , Modelos Moleculares , Pandemias , Neumonía Viral/enzimología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Sistema Renina-Angiotensina/inmunología , SARS-CoV-2RESUMEN
The virulence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the aggressive nature of the disease has transformed the universal pace of research in the desperate attempt to seek effective therapies to halt the morbidity and mortality of this pandemic. The rapid sequencing of the SARS-CoV-2 virus facilitated identification of the receptor for angiotensin converting enzyme 2 (ACE2) as the high affinity binding site that allows virus endocytosis. Parallel evidence that coronavirus disease 2019 (COVID-19) disease evolution shows greater lethality in patients with antecedent cardiovascular disease, diabetes, or even obesity questioned the potential unfavorable contribution of angiotensin converting enzyme (ACE) inhibitors or angiotensin II (Ang II) receptor blockers as facilitators of adverse outcomes due to the ability of these therapies to augment the transcription of Ace2 with consequent increase in protein formation and enzymatic activity. We review, here, the specific studies that support a role of these agents in altering the expression and activity of ACE2 and underscore that the robustness of the experimental data is associated with weak clinical long-term studies of the existence of a similar regulation of tissue or plasma ACE2 in human subjects.
Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/virología , Peptidil-Dipeptidasa A/efectos de los fármacos , Neumonía Viral/virología , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/enzimología , Humanos , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/enzimología , SARS-CoV-2 , Factores de TiempoRESUMEN
ACE2 is a type I membrane protein with extracellular carboxypeptidase activity displaying a broad tissue distribution with highest expression levels at the brush border membrane (BBM) of small intestine enterocytes and a lower expression in stomach and colon. In small intestinal mucosa, ACE2 mRNA expression appears to increase with age and to display higher levels in patients taking ACE-inhibitors (ACE-I). There, ACE2 protein heterodimerizes with the neutral amino acid transporter Broad neutral Amino acid Transporter 1 (B0AT1) (SLC6A19) or the imino acid transporter Sodium-dependent Imino Transporter 1 (SIT1) (SLC6A20), associations that are required for the surface expression of these transport proteins. These heterodimers can form quaternary structures able to function as binding sites for SARS-CoV-2 spike glycoproteins. The heterodimerization of the carboxypeptidase ACE2 with B0AT1 is suggested to favor the direct supply of substrate amino acids to the transporter, but whether this association impacts the ability of ACE2 to mediate viral infection is not known. B0AT1 mutations cause Hartnup disorder, a condition characterized by neutral aminoaciduria and, in some cases, pellagra-like symptoms, such as photosensitive rash, diarrhea, and cerebellar ataxia. Correspondingly, the lack of ACE2 and the concurrent absence of B0AT1 expression in small intestine causes a decrease in l-tryptophan absorption, niacin deficiency, decreased intestinal antimicrobial peptide production, and increased susceptibility to inflammatory bowel disease (IBD) in mice. Thus, the abundant expression of ACE2 in small intestine and its association with amino acid transporters appears to play a crucial role for the digestion of peptides and the absorption of amino acids and, thereby, for the maintenance of structural and functional gut integrity.
Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/enzimología , Absorción Intestinal , Mucosa Intestinal/enzimología , Proteínas de Transporte de Membrana/metabolismo , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/enzimología , Internalización del Virus , Enzima Convertidora de Angiotensina 2 , Animales , COVID-19 , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/metabolismo , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/virología , Multimerización de Proteína , SARS-CoV-2RESUMEN
Angiotensin converting enzyme (ACE) is well-known for its role in blood pressure regulation via the renin-angiotensin aldosterone system (RAAS) but also functions in fertility, immunity, haematopoiesis and diseases such as obesity, fibrosis and Alzheimer's dementia. Like ACE, the human homologue ACE2 is also involved in blood pressure regulation and cleaves a range of substrates involved in different physiological processes. Importantly, it is the functional receptor for severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 responsible for the 2020, coronavirus infectious disease 2019 (COVID-19) pandemic. Understanding the interaction between SARS-CoV-2 and ACE2 is crucial for the design of therapies to combat this disease. This review provides a comparative analysis of methodologies and findings to describe how structural biology techniques like X-ray crystallography and cryo-electron microscopy have enabled remarkable discoveries into the structure-function relationship of ACE and ACE2. This, in turn, has enabled the development of ACE inhibitors for the treatment of cardiovascular disease and candidate therapies for the treatment of COVID-19. However, despite these advances the function of ACE homologues in non-human organisms is not yet fully understood. ACE homologues have been discovered in the tissues, body fluids and venom of species from diverse lineages and are known to have important functions in fertility, envenoming and insect-host defence mechanisms. We, therefore, further highlight the need for structural insight into insect and venom ACE homologues for the potential development of novel anti-venoms and insecticides.
Asunto(s)
Betacoronavirus/patogenicidad , Infecciones por Coronavirus/enzimología , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/enzimología , Receptores Virales/metabolismo , Internalización del Virus , Enzima Convertidora de Angiotensina 2 , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Animales , Antivirales/uso terapéutico , Betacoronavirus/efectos de los fármacos , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Interacciones Huésped-Patógeno , Humanos , Pandemias , Peptidil-Dipeptidasa A/química , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Conformación Proteica , Receptores Virales/química , SARS-CoV-2 , Relación Estructura-Actividad , Tratamiento Farmacológico de COVID-19RESUMEN
Angiotensin-converting enzyme II (ACE2) is a homologue of angiotensin-converting enzyme discovered in 2000. From the initial discovery, it was recognized that the kidneys were organs very rich on ACE2. Subsequent studies demonstrated the precise localization of ACE2 within the kidney and the importance of this enzyme in the metabolism of Angiotensin II and the formation of Angiotensin 1-7. With the recognition early in 2020 of ACE2 being the main receptor of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2), the interest in this protein has dramatically increased. In this review, we will focus on kidney ACE2; its localization, its alterations in hypertension, diabetes, the effect of ACE inhibitors and angiotensin type 1 receptor blockers (ARBs) on ACE2 and the potential use of ACE2 recombinant proteins therapeutically for kidney disease. We also describe the emerging kidney manifestations of COVID-19, namely the frequent development of acute kidney injury. The possibility that binding of SARS-CoV-2 to kidney ACE2 plays a role in the kidney manifestations is also briefly discussed.