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1.
Infez Med ; 30(2): 231-241, 2022.
Article in English | MEDLINE | ID: covidwho-1980044

ABSTRACT

Coronavirus disease 2019 (COVID-19) has been spreading worldwide. Many COVID-19 patients were accompanied by myocardial injury during the course of the disease. To evaluate the association of cardiac injury with clinical outcomes in COVID-19 patients, we recruited 261 COVID-19 cases admitted to Tongji Hospital of Huazhong University of Science and Technology in this study. Compared with patients without myocardial injury, those with myocardial injury were older, with shorter hospital stays and lower survival rates. They also had higher levels of inflammatory biomarkers (Interleukin-6,8,10 and C-reactive protein), coagulation biomarkers, liver and kidney function markers. Kaplan-Meier analysis demonstrated that patients with myocardial injury had a higher mortality rate. The multivariate Cox regression model and the nomogram revealed that myocardial injury, co-morbidity, and abnormal procalcitonin (PCT) levels were independent risk factors of the mortality of COVID-19 patients. The linear correlation analysis and the ROC curve suggested a predictive value of the neutrophil-lymphocyte ratio (NLR) in cardiac injury. Summarily, myocardial injury in COVID-19 patients is associated with a higher mortality risk. Attention should be paid to monitoring myocardial injury in patients with significantly elevated myocardial markers and NLR at admission.

2.
Le infezioni in medicina ; 30(2):231-241, 2022.
Article in English | EuropePMC | ID: covidwho-1887878

ABSTRACT

SUMMARY Coronavirus disease 2019 (COVID-19) has been spreading worldwide. Many COVID-19 patients were accompanied by myocardial injury during the course of the disease. To evaluate the association of cardiac injury with clinical outcomes in COVID-19 patients, we recruited 261 COVID-19 cases admitted to Tongji Hospital of Huazhong University of Science and Technology in this study. Compared with patients without myocardial injury, those with myocardial injury were older, with shorter hospital stays and lower survival rates. They also had higher levels of inflammatory biomarkers (Interleukin-6,8,10 and C-reactive protein), coagulation biomarkers, liver and kidney function markers. Kaplan-Meier analysis demonstrated that patients with myocardial injury had a higher mortality rate. The multivariate Cox regression model and the nomogram revealed that myocardial injury, co-morbidity, and abnormal procalcitonin (PCT) levels were independent risk factors of the mortality of COVID-19 patients. The linear correlation analysis and the ROC curve suggested a predictive value of the neutrophil-lymphocyte ratio (NLR) in cardiac injury. Summarily, myocardial injury in COVID-19 patients is associated with a higher mortality risk. Attention should be paid to monitoring myocardial injury in patients with significantly elevated myocardial markers and NLR at admission.

3.
EuropePMC; 2022.
Preprint in English | EuropePMC | ID: ppcovidwho-335243

ABSTRACT

ABSTRACT As the COVID-19 pathogen, SARS-CoV-2 relies on its main protease (M Pro ) for pathogenesis and replication. During the crystallographic analyses of M Pro crystals that were exposed to the air, a uniquely Y-shaped, S-O-N-O-S-bridged posttranslational crosslink that connects three residues C22, C44, and K61 at their side chains was frequently observed. As a novel posttranslational modification, this crosslink serves as a redox switch to regulate the catalytic activity of M Pro , a demonstrated drug target of COVID-19. The formation of this linkage leads to a much more opened active site that can be potentially targeted for the development of novel SARS-CoV-2 antivirals. The inactivation of M Pro by this crosslink indicates that small molecules that lock M Pro in the crosslinked form can be potentially used with other active site-targeting molecules such as paxlovid for synergistic effects in inhibiting the SARS-CoV-2 viral replication. Therefore, this new finding reveals a unique aspect of the SARS-CoV-2 pathogenesis and is potentially paradigm-shifting in our current understanding of the function of M Pro and the development of its inhibitors as COVID-19 antivirals.

4.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-324689

ABSTRACT

The outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a worldwide public health crisis. When the SARS-CoV-2 enters the biological fluids in the human body, different types of biomolecules (in particular proteins) may adsorb on its surface and alter its infection ability. Although great efforts have recently been devoted to the interaction of the specific antibodies with the SARS-CoV-2, it still remains largely unknown how the other serum proteins affect the infection of the SARS-CoV-2. In this work, we systematically investigate the interaction of serum proteins with the SARS-CoV-2 RBD by the molecular docking and the all-atom molecular dynamics simulations. It is found that the non-specific immunoglobulin (Ig) indeed cannot effectively bind to the SARS-CoV-2 RBD while the human serum albumin (HSA) may have some potential of blocking its infection (to ACE2). More importantly, we find that the RBD can cause the significant structural change of the Apolipoprotein E (ApoE), by which SARS-CoV-2 may hijack the metabolic pathway of the ApoE to facilitate its cell entry. The present study enhances the understanding of the role of protein corona in the bio-behaviors of SARS-CoV-2, which may aid the more precise and personalized treatment for COVID-19 infection in the clinic.

5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-309525

ABSTRACT

The spread of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a global health crisis. The binding affinity of SARS-CoV-2 (in particular the receptor binding domain, RBD) to its receptor angiotensin converting enzyme 2 (ACE2) and the antibodies is of great importance in understanding the infectivity of COVID-19 and evaluating the candidate therapeutic for COVID-19. In this work, we propose a new method based on molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) to accurately calculate the free energy of SARS-CoV-2 RBD binding to ACE2 and antibodies. The calculated binding free energy of SARS-CoV-2 RBD to ACE2 is -13.3 kcal/mol, and that of SARS-CoV RBD to ACE2 is -11.4 kcal/mol, which agrees well with experimental result (-11.3 kcal/mol and -10.1 kcal/mol, respectively). Moreover, we take two recently reported antibodies as the example, and calculate the free energy of antibodies binding to SARS-CoV-2 RBD, which is also consistent with the experimental findings. Further, within the framework of the modified MM/PBSA, we determine the key residues and the main driving forces for the SARS-CoV-2 RBD/CB6 interaction by the computational alanine scanning method. The present study offers a computationally efficient and numerically reliable method to evaluate the free energy of SARS-CoV-2 binding to other proteins, which may stimulate the development of the therapeutics against the COVID-19 disease in real applications.

6.
Dalton Trans ; 50(35): 12226-12233, 2021 Sep 14.
Article in English | MEDLINE | ID: covidwho-1358359

ABSTRACT

Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2Mpro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC50, for SC2Mpro in the 8-34 µM range, the IC50 values are ca. 100 nM for Zn(NO3)2 which are further enhanced in Zn-L combinations (59-97 nM). Isolation of the Zn(L)2 binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2Mpro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-L combinations orient so as to permit dative bonding of Zn(L)+ to basic active site residues.


Subject(s)
COVID-19/drug therapy , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Tropolone/pharmacology , Zinc/pharmacology , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/virology , Catalytic Domain/drug effects , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Humans , Ligands , Models, Molecular , Molecular Docking Simulation , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Tropolone/analogs & derivatives , Zinc/chemistry
7.
Nanoscale ; 13(30): 12865-12873, 2021 Aug 14.
Article in English | MEDLINE | ID: covidwho-1307348

ABSTRACT

The outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a worldwide public health crisis. When the SARS-CoV-2 enters the biological fluids in the human body, different types of biomolecules (in particular proteins) may adsorb on its surface and alter its infection ability. Although great efforts have recently been devoted to the interaction of specific antibodies with the SARS-CoV-2, it still remains largely unknown how the other serum proteins affect the infection of the SARS-CoV-2. In this work, we systematically investigate the interaction of serum proteins with the SARS-CoV-2 RBD by molecular docking and all-atom molecular dynamics simulations. It is found that non-specific immunoglobulins (Ig) indeed cannot effectively bind to the SARS-CoV-2 RBD while human serum albumin (HSA) may have some potential in blocking its infection (to ACE2). More importantly, we find that the RBD can cause significant structural changes in Apolipoprotein E (ApoE), by which SARS-CoV-2 may hijack the metabolic pathway of ApoE to facilitate its cell entry. The present study enhances the understanding of the role of protein corona in the bio-behaviors of SARS-CoV-2, which may aid the more precise and personalized treatment for COVID-19 infection in the clinic.


Subject(s)
COVID-19 , SARS-CoV-2 , Blood Proteins , Humans , Molecular Docking Simulation , Protein Binding , Spike Glycoprotein, Coronavirus/metabolism
8.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-4081

ABSTRACT

In Dec. 2019, Corona Virus Disease 2019 (COVID-19) broke out in Wuhan, Hubei Province, China, and spread rapidly to other areas. COVID-19 patients with cardiovascular disease are the most of all comorbidities, and SARS-CoV-2 infection poses a serious threat to cardiovascular disease, antiviral drugs also have series of adverse effects on the cardiovascular system. These bring great challenges to the treatment of COVID-19 patients with cardiovascular disease. This article combines the common adverse reactions and interactions of antiviral drugs and cardiovascular drugs to formulate pharmacol. monitoring, provides a reference for the treatment of COVID-19 patients with cardiovascular disease, promote the safety, rationality and effectiveness of clin. medication.

9.
SciFinder; 2020.
Preprint | SciFinder | ID: ppcovidwho-3575

ABSTRACT

A review. At present, the diagnosis and treatment of corona virus disease 2019 (COVID-19) has entered a critical period. The treatment of complex and changeable disease requires the cooperation of doctors, nurses and pharmacists. Therefore, from the perspective of pharmaceutical service, this article introduced some important aspects to improve the treatment of COVID-19, including the formulation of pharmaceutical care standards, prescription and medical order review, remote pharmaceutical care for COVID-19, pharmaceutical care for COVID-19 patients in the hospital and science popularization of COVID-19. As an important part of the prevention and control of epidemic disease, clin. pharmacy service has played an active role in ensuring the safety and effectiveness of patients′ medication, thereby making contribution to the effective control of the epidemic.

10.
ChemMedChem ; 16(6): 942-948, 2021 03 18.
Article in English | MEDLINE | ID: covidwho-959133

ABSTRACT

The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro ) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro ), we have designed and synthesized a series of SC2MPro inhibitors that contain ß-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active-site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 µM and A549/ACE2 cells at 0.16-0.31 µM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra-high antiviral potency.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , A549 Cells , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/metabolism , Catalytic Domain , Chlorocebus aethiops , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Cysteine/chemistry , Cysteine Proteinase Inhibitors/chemical synthesis , Cysteine Proteinase Inhibitors/metabolism , Humans , Microbial Sensitivity Tests , Protein Binding , Pyrrolidinones/chemical synthesis , Pyrrolidinones/metabolism , Pyrrolidinones/pharmacology , SARS-CoV-2/enzymology , Vero Cells
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