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Infect Genet Evol ; 85: 104419, 2020 Jun 12.
Artigo em Inglês | MEDLINE | ID: covidwho-597588

RESUMO

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is a current global threat for which there is an urgent need to search for an effective therapy. The transmembrane spike (S) glycoprotein of SARS-CoV-2 directly binds to the host angiotensin-converting enzyme 2 (ACE2) and mediates viral entrance, which is therefore considered as a promising drug target. Considering that new drug development is a time-consuming process, drug repositioning may facilitate rapid drug discovery dealing with sudden infectious diseases. Here, we compared the differences between the virtual structural proteins of SARS-CoV-2 and SARS-CoV, and selected a pocket mainly localizing in the fusion cores of S2 domain for drug screening. A virtual drug design algorithm screened the Food and Drug Administration-approved drug library of 1234 compounds, and 13 top scored compounds were obtained through manual screening. Through in vitro molecular interaction experiments, eltrombopag was further verified to possess a high binding affinity to S protein plus human ACE2 and could potentially affect the stability of the ACE2-S protein complex. Hence, it is worth further exploring eltrombopag as a potential drug for the treatment of SARS-CoV-2 infection.

3.
Arthritis Rheumatol ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: covidwho-621296

RESUMO

OBJECTIVES: Coagulopathy is one of the characteristics of critically ill patients with Coronavirus Disease 2019 (COVID-19). Antiphospholipid antibodies (aPLs) contribute to coagulopathy, but their role in COVID-19 remains unclear. We aimed to determine the prevalence and characteristics of aPLs in patients with COVID-19. METHODS: Sera collected from 66 critically ill and 13 non-critically ill patients with COVID-19 were tested for anti-cardiolipin (aCL) and anti-ß2-glycoprotein 1 (aß2GP1) (IgG, IgM, and IgA) and IgG aß2GP1-D1 by the chemiluminescence assay (CIA) and IgM and IgG anti-phosphatidylserine/prothrombin (aPS/PT) by ELISA. RESULTS: aPLs were detected in 47.0% of critically ill patients (31/66), but not in patients with non-critical conditions. IgA aß2GP1 was the most common aPL, present in 28.8% (19/66) critically ill patients, followed by IgA aCL (25.8%,17/66) and IgG aß2GP1 (18.2%,12/66). For multiple aPLs, IgA aß2GP1+IgA aCL was the most common type (22.7%, 15/66), followed by IgA aß2GP1+IgA aCL+ IgG aß2GP1 (15.2%, 10/66). aPLs emerge around 35-39 days post-disease onset. Dynamic analysis of aPLs revealed 4 patterns based on persistence or transient appearance of the aPLs. Patients with multiple aPLs displayed significantly higher incidence of cerebral infarction (p=0.023). CONCLUSIONS: aPLs were common in critically ill patients. Multiple medium or high levels aPLs may help identify patients at risk of developing cerebral infarction. aPLs may be transient and disappear within a few weeks, but in genetically predisposed patients, COVID-19 may trigger the development of "COVID-19-induced-APS-like-syndrome". Long-term follow-up on COVID-19 patients positive for aPLs would be of great importance.

4.
Eur J Heart Fail ; 2020 May 28.
Artigo em Inglês | MEDLINE | ID: covidwho-401833

RESUMO

The Coronavirus Disease 2019 (COVID-19) pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is causing considerable morbidity and mortality worldwide. Multiple reports have suggested that patients with heart failure (HF) are at a higher risk of severe disease and mortality with COVID-19. Moreover, evaluating and treating HF patients with comorbid COVID-19 represents a formidable clinical challenge as symptoms of both conditions may overlap and they may potentiate each other. Limited data exist regarding comprehensive management of HF patients with concomitant COVID-19. Since these issues pose serious new challenges for clinicians worldwide, HF specialists must develop a structured approach to the care of patients with COVID-19 and be included early in the care of these patients. Therefore, the Heart Failure Association of the European Society of Cardiology and Chinese Heart Failure Association & National Heart Failure Committee conducted web-based meetings to discuss these unique clinical challenges and reach a consensus opinion to help providers worldwide deliver better patient care. The main objective of this position paper is to outline the management of HF patients with concomitant COVID-19 based on the available data and personal experiences of physicians from Asia, Europe and United States. This article is protected by copyright. All rights reserved.

5.
Front Cardiovasc Med ; 2020.
Artigo | COVIDWHO | ID: covidwho-337046

RESUMO

In December 2019, Coronavirus Disease 2019 (COVID-19) caused by SARS-CoV-2, occurred in China and has currently led to a global pandemic In addition to respiratory involvement, COVID-19 was also associated with significant multiple organ dysfunction syndrome (MODS) Cardiovascular impairment has been observed and is now drawing growing attention Cardiovascular protective strategies are urgent and of great significance to the overall prognosis of COVID-19 patients Direct viral infection, cytokine storm, and aggravation of existing cardiovascular diseases were recognized as possible mechanisms of cardiovascular impairment in COVID-19 Hyperactivated inflammation plays an important role in all three mechanisms and is considered to be fundamental in the development of cardiovascular impairment and MODS in COVID-19 Therefore, in addition to conventional cardiovascular treatment, anti-inflammatory therapy is a reasonable strategy for severe cases to further enhance cardiovascular protection and potentially mitigate MODS We reviewed the inflammatory features and current promising treatments of COVID-19 as well as cardiovascular anti-inflammatory therapies that have been verified in previous clinical trials with positive outcomes We believe that targeting the central pathway (IL-1beta, TNF-alpha, IL-6), balancing the Th1 and Th2 response, and administering long-term anti-inflammatory therapy might be promising prospects to reduce cardiovascular impairment and even MODS during the acute and recovery phases of COVID-19 The cardiovascular anti-inflammatory therapies might be of great application value to the management of COVID-19 patients and we further propose an algorithm for the selection of anti-inflammatory therapy for COVID-19 patients with or at high risk of cardiovascular impairment We recommend to take the experiences in cardiovascular anti-inflammatory therapy as references in the management of COVID-19 and conduct related clinical trials, while the clinical translation of novel treatments from preclinical studies or in vitro drug screening should proceed with caution due to unguaranteed efficacy and safety profiles

6.
Science ; 368(6498): 1499-1504, 2020 06 26.
Artigo em Inglês | MEDLINE | ID: covidwho-154668

RESUMO

The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global crisis. Replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp) enzyme, a target of the antiviral drug remdesivir. Here we report the cryo-electron microscopy structure of the SARS-CoV-2 RdRp, both in the apo form at 2.8-angstrom resolution and in complex with a 50-base template-primer RNA and remdesivir at 2.5-angstrom resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp, where remdesivir is covalently incorporated into the primer strand at the first replicated base pair, and terminates chain elongation. Our structures provide insights into the mechanism of viral RNA replication and a rational template for drug design to combat the viral infection.

9.
Clin Immunol ; 214: 108393, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-41645

RESUMO

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Cloroquina/uso terapêutico , Citocinas/imunologia , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Inflamação/patologia , Interleucina-6/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Pandemias , Trombose/virologia , Vasculite/virologia
12.
Clin Immunol ; 214: 108393, 2020 05.
Artigo em Inglês | MEDLINE | ID: covidwho-15221

RESUMO

The pandemic outbreak of coronavirus disease 2019 (COVID-19) is rapidly spreading all over the world. Reports from China showed that about 20% of patients developed severe disease, resulting in a fatality of 4%. In the past two months, we clinical immunologists participated in multi-rounds of MDT (multidiscipline team) discussion on the anti-inflammation management of critical COVID-19 patients, with our colleagues dispatched from Chinese leading PUMC Hospital to Wuhan to admit and treat the most severe patients. Here, from the perspective of clinical immunologists, we will discuss the clinical and immunological characteristics of severe patients, and summarize the current evidence and share our experience in anti-inflammation treatment, including glucocorticoids, IL-6 antagonist, JAK inhibitors and choloroquine/hydrocholoroquine, of patients with severe COVID-19 that may have an impaired immune system.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Cloroquina/uso terapêutico , Citocinas/imunologia , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Inflamação/patologia , Interleucina-6/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Pandemias , Trombose/virologia , Vasculite/virologia
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