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1.
J Med Chem ; 65(3): 2558-2570, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1655430

ABSTRACT

Safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are the best approach to successfully combat the COVID-19 pandemic. The receptor-binding domain (RBD) of the viral spike protein is a major target to develop candidate vaccines. α-Galactosylceramide (αGalCer), a potent invariant natural killer T cell (iNKT) agonist, was site-specifically conjugated to the N-terminus of the RBD to form an adjuvant-protein conjugate, which was anchored on the liposome surface. This is the first time that an iNKT cell agonist was conjugated to the protein antigen. Compared to the unconjugated RBD/αGalCer mixture, the αGalCer-RBD conjugate induced significantly stronger humoral and cellular responses. The conjugate vaccine also showed effective cross-neutralization to all variants of concern (B.1.1.7/alpha, B.1.351/beta, P.1/gamma, B.1.617.2/delta, and B.1.1.529/omicron). These results suggest that the self-adjuvanting αGalCer-RBD has great potential to be an effective COVID-19 vaccine candidate, and this strategy might be useful for designing various subunit vaccines.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/therapy , Galactosylceramides/therapeutic use , Peptide Fragments/therapeutic use , SARS-CoV-2/immunology , Vaccines, Conjugate/therapeutic use , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/therapeutic use , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Female , Galactosylceramides/chemistry , Galactosylceramides/immunology , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Interferon-gamma/metabolism , Liposomes/chemistry , Liposomes/immunology , Liposomes/therapeutic use , Mice, Inbred BALB C , Peptide Fragments/chemistry , Peptide Fragments/immunology , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/therapeutic use , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunology
2.
Ann Emerg Med ; 78(4): 511-514, 2021 10.
Article in English | MEDLINE | ID: covidwho-1293546

ABSTRACT

Vaccine-induced thrombotic thrombocytopenia is a newly described disease process in the setting of expanding access to COVID-19 vaccination. The United States Centers for Disease Control and Prevention recommends treatment with an alternative to heparin in patients suspected of having vaccine-induced thrombotic thrombocytopenia. At this time there have been no reported outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. We describe the early outcomes from the treatment of vaccine-induced thrombotic thrombocytopenia with bivalirudin as a heparin alternative. A 40-year-old Caucasian woman was found to have thrombocytopenia, cerebral venous sinus thrombosis, and pulmonary embolism following vaccination for COVID-19 with Ad26.COV2.S. She exhibited a steady rise in platelet count: 20×109/L at hospital day 0, 115×109/L at discharge on hospital day 6, and 182×109/L on outpatient follow-up on day 9. While the patient exhibited a transient drop in hemoglobin, there was no clinical evidence of bleeding. This patient did not demonstrate any clinical sequelae of thrombosis, and she reported resolution of her headache. Vaccination with Ad26.COV2.S appears to be associated with a small but significant risk for thrombotic thrombocytopenia within 13 days of receipt. The Centers for Disease Control and Prevention guidance to consider an alternative to heparin was not accompanied by specifically recommended alternatives. A single patient treated with bivalirudin for suspected vaccine-induced thrombotic thrombocytopenia subsequently experienced symptom improvement and a rise in platelet count and did not demonstrate any immediate negative outcomes. A provider may consider bivalirudin as an alternative to heparin in patients with suspected vaccine-induced thrombotic thrombocytopenia following Ad26.COV2.S vaccination, pending more definitive research.


Subject(s)
COVID-19 Vaccines/adverse effects , Fibrinolytic Agents/therapeutic use , Peptide Fragments/therapeutic use , Sinus Thrombosis, Intracranial/drug therapy , Thrombocytopenia/drug therapy , Adult , Blood Chemical Analysis , Blood Physiological Phenomena , COVID-19/prevention & control , Female , Hirudins , Humans , Pulmonary Embolism/drug therapy , Pulmonary Embolism/etiology , Recombinant Proteins/therapeutic use , Sinus Thrombosis, Intracranial/etiology , Thrombocytopenia/etiology
3.
J Agric Food Chem ; 68(49): 14402-14408, 2020 Dec 09.
Article in English | MEDLINE | ID: covidwho-1023816

ABSTRACT

IRW (Ile-Arg-Trp) was identified as an inhibitor of angiotensin converting enzyme (ACE) from egg white protein ovotransferrin through an integrated in silico digestion and quantitative structure and activity relationship prediction in 2011. Oral administration of IRW to spontaneously hypertensive rats (SHRs) can significantly reduce blood pressure, via upregulation of ACE2, but not through the inhibition of ACE. ACE2 converts Ang II into Ang (1-7), thus lowering blood pressure via Mas receptor (MasR); coinfusion of Mas receptor antagonist A779 and IRW in SHRs abolished blood pressure-lowering effect of IRW, supporting a key role of ACE2/Ang (1-7)/MasR axis. Our ongoing study further established new roles of IRW as an antioxidant, an anti-inflammatory agent, an insulin sensitizer, and a bone cell anabolic. Future studies are warranted to understand the unique structure features of this peptide, its mechanisms of action at various targets, its bioavailability and metabolism, and its possible roles toward COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/metabolism , Conalbumin/pharmacology , Enzyme Activators/pharmacology , Oligopeptides/pharmacology , Peptide Fragments/pharmacology , Animals , Cell Line , Conalbumin/therapeutic use , Enzyme Activators/therapeutic use , Humans , Oligopeptides/therapeutic use , Peptide Fragments/therapeutic use , SARS-CoV-2/metabolism , Virus Attachment
4.
J Neuroimmune Pharmacol ; 16(1): 59-70, 2021 03.
Article in English | MEDLINE | ID: covidwho-1018438

ABSTRACT

COVID-19 is an infectious respiratory illness caused by the virus strain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and until now, there is no effective therapy against COVID-19. Since SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) for entering into host cells, to target COVID-19 from therapeutic angle, we engineered a hexapeptide corresponding to the ACE2-interacting domain of SARS-CoV-2 (AIDS) that inhibits the association between receptor-binding domain-containing spike S1 and ACE-2. Accordingly, wild type (wt), but not mutated (m), AIDS peptide inhibited SARS-CoV-2 spike S1-induced activation of NF-κB and expression of IL-6 in human lungs cells. Interestingly, intranasal intoxication of C57/BL6 mice with recombinant SARS-CoV-2 spike S1 led to fever, increase in IL-6 in lungs, infiltration of neutrophils into the lungs, arrhythmias, and impairment in locomotor activities, mimicking some of the important symptoms of COVID-19. However, intranasal treatment with wtAIDS, but not mAIDS, peptide reduced fever, protected lungs, improved heart function, and enhanced locomotor activities in SARS-CoV-2 spike S1-intoxicated mice. Therefore, selective targeting of ACE2-to-SARS-CoV-2 interaction by wtAIDS may be beneficial for COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Fever/drug therapy , Fever/etiology , Heart Diseases/etiology , Heart Diseases/prevention & control , Inflammation/drug therapy , Inflammation/etiology , Lung Diseases/etiology , Lung Diseases/prevention & control , Peptide Fragments/therapeutic use , Administration, Intranasal , Animals , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/prevention & control , COVID-19/pathology , Female , Heart Diseases/pathology , Interleukin-6/metabolism , Lung Diseases/pathology , Male , Mice , Mice, Inbred C57BL , Motor Activity/drug effects , Neutrophil Infiltration/drug effects , Spike Glycoprotein, Coronavirus/toxicity
6.
J Renin Angiotensin Aldosterone Syst ; 21(4): 1470320320972018, 2020.
Article in English | MEDLINE | ID: covidwho-917884

ABSTRACT

In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).


Subject(s)
Angiotensin I/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/complications , Peptide Fragments/therapeutic use , Pneumonia, Viral/complications , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/virology , Angiotensin I/physiology , Angiotensin-Converting Enzyme 2 , Animals , COVID-19 , Coronavirus Infections/mortality , Humans , Pandemics , Peptide Fragments/physiology , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/mortality , Renin-Angiotensin System/drug effects , Renin-Angiotensin System/physiology , SARS-CoV-2
7.
ACS Chem Neurosci ; 11(22): 3701-3703, 2020 11 18.
Article in English | MEDLINE | ID: covidwho-899862

ABSTRACT

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


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Drug Design , Peptide Fragments/therapeutic use , Pneumonia, Viral/drug therapy , Amino Acid Sequence , Antiviral Agents/metabolism , Betacoronavirus/drug effects , Betacoronavirus/genetics , COVID-19 , Coronavirus Infections/genetics , Coronavirus Infections/metabolism , Humans , Pandemics , Peptide Fragments/genetics , Peptide Fragments/metabolism , Pneumonia, Viral/genetics , Pneumonia, Viral/metabolism , Protein Binding/physiology , SARS-CoV-2 , Sequence Analysis, Protein/methods
8.
Trials ; 21(1): 769, 2020 Sep 07.
Article in English | MEDLINE | ID: covidwho-748922

ABSTRACT

OBJECTIVES: To assess the effect of anticoagulation with bivalirudin administered intravenously on gas-exchange in patients with COVID-19 and respiratory failure using invasive mechanical ventilation. TRIAL DESIGN: This is a single centre parallel group, superiority, randomized (1:1 allocation ratio) controlled trial. PARTICIPANTS: All patients admitted to the Hamad Medical Corporation -ICU in Qatar for COVID-19 associated respiratory distress and in need of mechanical ventilation are screened for eligibility. INCLUSION CRITERIA: all adult patients admitted to the ICU who test positive for COVID-19 by PCR-test and in need for mechanical ventilation are eligible for inclusion. Upon crossing the limit of D-dimers (1.2 mg/L) these patients are routinely treated with an increased dose of anticoagulant according to our local protocol. This will be the start of randomization. EXCLUSION CRITERIA: pregnancy, allergic to the drug, inherited coagulation abnormalities, no informed consent. INTERVENTION AND COMPARATOR: The intervention group will receive the anticoagulant bivalirudin intravenously with a target aPTT of 45-70 sec for three days while the control group will stay on the standard treatment with low-molecular-weight heparins /unfractionated heparin subcutaneously (see scheme in Additional file 1). All other treatment will be unchanged and left to the attending physicians. MAIN OUTCOMES: As a surrogate parameter for clinical improvement and primary outcome we will use the PaO2/FiO2 (P/F) ratio. RANDOMISATION: After inclusion, the patients will be randomized using a closed envelope method into the conventional treatment group, which uses the standard strategy and the experimental group which receives anticoagulation treatment with bivalirudin using an allocation ratio of 1:1. BLINDING (MASKING): Due to logistical and safety reasons (assessment of aPTT to titrate the study drug) only the data-analyst will be blinded to the groups. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): We performed a sample size calculation and assumed the data for P/F ratio (according to literature) is normally distributed and used the mean which would be: 160 and SD is 80. We expect the treatment will improve this by 30%. In order to reach a power of 80% we would need 44 patients per group (in total 88 patients). Taking approximately 10% of dropout into account we will include 100 patients (50 in each group). TRIAL STATUS: The local registration number is MRC-05-082 with the protocol version number 2. The date of approval is 18th June 2020. Recruitment started on 28th June and is expected to end in November 2020. TRIAL REGISTRATION: The protocol is registered before starting subject recruitment under the title: "Anticoagulation in patients suffering from COVID-19 disease. The ANTI-CO Trial" in ClinicalTrials.org with the registration number: NCT04445935 . Registered on 24 June 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 2). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Subject(s)
Antithrombins/therapeutic use , Coronavirus Infections/drug therapy , Peptide Fragments/therapeutic use , Pneumonia, Viral/drug therapy , Respiration, Artificial , Respiratory Distress Syndrome/therapy , Anticoagulants/therapeutic use , Betacoronavirus , COVID-19 , Coronavirus Infections/blood , Critical Illness , Fibrin Fibrinogen Degradation Products/metabolism , Heparin/therapeutic use , Heparin, Low-Molecular-Weight/therapeutic use , Hirudins , Humans , Pandemics , Partial Thromboplastin Time , Pneumonia, Viral/blood , Qatar , Recombinant Proteins/therapeutic use , SARS-CoV-2
9.
J Cardiovasc Pharmacol ; 76(4): 397-406, 2020 10.
Article in English | MEDLINE | ID: covidwho-706197

ABSTRACT

The ongoing COVID-19 pandemic has produced serious turmoil world-wide. Lung injury causing acute respiratory distress syndrome seems to be a most dreaded complication occurring in ∼30%. Older patients with cardiovascular comorbidities and acute respiratory distress syndrome have an increased mortality. Although the precise mechanisms involved in the development of lung injury have not been fully elucidated, the role of the extended renin-angiotensin system seems to be pivotal. In this context, angiotensin-converting enzyme 2 (ACE2), an angiotensin-converting enzyme homologue, has been recognized as a facilitator of viral entry into the host, albeit its involvement in other counter-regulatory effects, such as converting angiotensin (Ang) II into Ang 1-7 with its known protective actions. Thus, concern was raised that the use of renin-angiotensin system inhibitors by increasing ACE2 expression may enhance patient susceptibility to the COVID-19 virus. However, current data have appeased such concerns because there has been no clinical evidence of a harmful effect of these agents as based on observational studies. However, properly designed future studies will be needed to further confirm or refute current evidence. Furthermore, other pathways may also play important roles in COVID-19 transmission and pathogenesis; spike (S) protein proteases facilitate viral transmission by cleaving S protein that promotes viral entry into the host; neprilysin (NEP), a neutral endopeptidase known to cleave natriuretic peptides, degrades Ang I into Ang 1-7; NEP can also catabolize bradykinin and thus mitigate bradykinin's role in inflammation, whereas, in the same context, specific bradykinin inhibitors may also negate bradykinin's harmful effects. Based on these intricate mechanisms, various preventive and therapeutic strategies may be devised, such as upregulating ACE2 and/or using recombinant ACE2, and exploiting the NEP, bradykinin and serine protease pathways, in addition to anti-inflammatory and antiviral therapies. These issues are herein reviewed, available studies are tabulated and pathogenetic mechanisms are pictorially illustrated.


Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Renin-Angiotensin System/drug effects , Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , COVID-19 , Humans , Pandemics , Peptide Fragments/therapeutic use , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/therapeutic use , Recombinant Proteins/therapeutic use , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism
10.
Br J Pharmacol ; 177(17): 3898-3904, 2020 09.
Article in English | MEDLINE | ID: covidwho-669062

ABSTRACT

Inflammation is generally accepted as a component of the host defence system and a protective response in the context of infectious diseases. However, altered inflammatory responses can contribute to disease in infected individuals. Many endogenous mediators that drive the resolution of inflammation are now known. Overall, mediators of resolution tend to decrease inflammatory responses and provide normal or greater ability of the host to deal with infection. In the lung, it seems that pro-resolution molecules, or strategies that promote their increase, tend to suppress inflammation and lung injury and facilitate control of bacterial or viral burden. Here, we argue that the demonstrated anti-inflammatory, pro-resolving, anti-thrombogenic and anti-microbial effects of such endogenous mediators of resolution may be useful in the treatment of the late stages of the disease in patients with COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , COVID-19/drug therapy , Inflammation/drug therapy , Acetates/therapeutic use , Angiotensin I/therapeutic use , Animals , Annexin A1/therapeutic use , COVID-19/immunology , Disease Models, Animal , Docosahexaenoic Acids/therapeutic use , Humans , Hydrogen Peroxide/therapeutic use , Inflammation/immunology , Inflammation Mediators/immunology , Mice , Orthomyxoviridae Infections/drug therapy , Orthomyxoviridae Infections/immunology , Oxidants/therapeutic use , Peptide Fragments/therapeutic use , Peptides/therapeutic use , Phosphodiesterase 4 Inhibitors/therapeutic use , Pneumonia, Viral/drug therapy , Pneumonia, Viral/immunology , Rolipram/therapeutic use , Vasodilator Agents/therapeutic use
11.
J Cardiothorac Vasc Anesth ; 35(4): 1149-1153, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-650635

ABSTRACT

In its severe manifestation, coronavirus disease 2019 (COVID-19) compromises oxygenation in a manner that is refractory to maximal conventional support and requires escalation to extracorporeal membrane oxygenation (ECMO). Maintaining ECMO support for extended durations requires a delicately balanced anticoagulation strategy to maintain circuit viability by preventing thrombus deposition while avoiding excessive anticoagulation yielding hemorrhage-a task that is complicated in COVID-19 secondary to an inherent hypercoagulable state. Bivalirudin, a member of the direct thrombin inhibitor drug class, offers potential advantages during ECMO, including to its ability to exert its effect by directly attaching to and inhibiting freely circulating and fibrin-bound thrombin. Herein, the successful use of an anticoagulation strategy using the off-label use of a continuous infusion of bivalirudin in a case of severe hypoxemic and hypercarbic respiratory failure caused by COVID-19 requiring venovenous ECMO is reported. Importantly, therapeutic anticoagulation intensity was achieved rapidly with stable pharmacokinetics, and there was no need for any circuit interventions throughout the patient's 27-day ECMO course. In COVID-19, bivalirudin offers a potential option for maintaining systemic anticoagulation during ECMO in a manner that may mitigate the prothrombotic nature of the underlying pathophysiologic state.


Subject(s)
Anticoagulants/administration & dosage , Antithrombins/administration & dosage , COVID-19/diagnosis , COVID-19/therapy , Extracorporeal Membrane Oxygenation/adverse effects , Hirudins/administration & dosage , Peptide Fragments/administration & dosage , Thrombosis/prevention & control , Aged , Anticoagulants/therapeutic use , Antithrombins/therapeutic use , COVID-19/complications , COVID-19 Nucleic Acid Testing , Female , Humans , Peptide Fragments/therapeutic use , Polymerase Chain Reaction , Recombinant Proteins/administration & dosage , Recombinant Proteins/therapeutic use , Respiratory Insufficiency/etiology , Respiratory Insufficiency/therapy , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Treatment Outcome
12.
Biochem Pharmacol ; 178: 114057, 2020 08.
Article in English | MEDLINE | ID: covidwho-378094

ABSTRACT

COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/prevention & control , Drug Repositioning/methods , Neprilysin/antagonists & inhibitors , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Signal Transduction/drug effects , Angiotensin I/pharmacology , Angiotensin I/therapeutic use , Angiotensin Receptor Antagonists/pharmacology , Angiotensin Receptor Antagonists/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/pharmacology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/physiopathology , Coronavirus Infections/virology , Drug Repositioning/statistics & numerical data , Drug Repositioning/trends , Humans , Neprilysin/metabolism , Peptide Fragments/pharmacology , Peptide Fragments/therapeutic use , Pneumonia, Viral/physiopathology , Pneumonia, Viral/virology , SARS-CoV-2
13.
Int Arch Allergy Immunol ; 181(6): 467-475, 2020.
Article in English | MEDLINE | ID: covidwho-235502

ABSTRACT

After the advent of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the outbreak of coronavirus disease 2019 (COVID-19) commenced across the world. Understanding the Immunopathogenesis of COVID-19 is essential for interrupting viral infectivity and preventing aberrant immune responses before a vaccine can be developed. In this review, we provide the latest insights into the roles of angiotensin-converting enzyme II (ACE2) and Ang II receptor-1 (AT1-R) in this disease. Novel therapeutic strategies, including recombinant ACE2, ACE inhibitors, AT1-R blockers, and Ang 1-7 peptides, may prevent or reduce viruses-induced pulmonary, cardiac, and renal injuries. However, more studies are needed to clarify the efficacy of these therapeutics. Furthermore, considering the common role of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway in AT1-R expressed on peripheral tissues and cytokine receptors on the surface of immune cells, potential targeting of this pathway using JAK inhibitors (JAKinibs) is suggested as a promising approach in patients with COVID-19 who are admitted to hospitals. In addition to antiviral therapy, potential ACE2- and AT1-R-inhibiting strategies, and other supportive care, we suggest other potential JAKinibs and novel anti-inflammatory combination therapies that affect the JAK-STAT pathway in patients with COVID-19. Since the combination of MTX and baricitinib leads to outstanding clinical outcomes, the addition of baricitinib to MTX might be a potential strategy.


Subject(s)
Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Azetidines/therapeutic use , Coronavirus Infections/drug therapy , Janus Kinases/genetics , Methotrexate/therapeutic use , Pandemics , Peptide Fragments/therapeutic use , Pneumonia, Viral/drug therapy , Sulfonamides/therapeutic use , Angiotensin-Converting Enzyme 2 , Betacoronavirus/drug effects , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Disease Progression , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Janus Kinases/antagonists & inhibitors , Janus Kinases/immunology , Molecular Targeted Therapy/methods , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/immunology , Pneumonia, Viral/epidemiology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Purines , Pyrazoles , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/immunology , SARS-CoV-2 , STAT Transcription Factors/antagonists & inhibitors , STAT Transcription Factors/genetics , STAT Transcription Factors/immunology , Signal Transduction/genetics , Signal Transduction/immunology
14.
J Med Virol ; 92(7): 726-730, 2020 07.
Article in English | MEDLINE | ID: covidwho-17559

ABSTRACT

This article reviews the correlation between angiotensin-converting enzyme 2 (ACE2) and severe risk factors for coronavirus disease 2019 (COVID-19) and the possible mechanisms. ACE2 is a crucial component of the renin-angiotensin system (RAS). The classical RAS ACE-Ang II-AT1R regulatory axis and the ACE2-Ang 1-7-MasR counter-regulatory axis play an essential role in maintaining homeostasis in humans. ACE2 is widely distributed in the heart, kidneys, lungs, and testes. ACE2 antagonizes the activation of the classical RAS system and protects against organ damage, protecting against hypertension, diabetes, and cardiovascular disease. Similar to SARS-CoV, SARS-CoV-2 also uses the ACE2 receptor to invade human alveolar epithelial cells. Acute respiratory distress syndrome (ARDS) is a clinical high-mortality disease, and ACE2 has a protective effect on this type of acute lung injury. Current research shows that the poor prognosis of patients with COVID-19 is related to factors such as sex (male), age (>60 years), underlying diseases (hypertension, diabetes, and cardiovascular disease), secondary ARDS, and other relevant factors. Because of these protective effects of ACE2 on chronic underlying diseases and ARDS, the development of spike protein-based vaccine and drugs enhancing ACE2 activity may become one of the most promising approaches for the treatment of COVID-19 in the future.


Subject(s)
Betacoronavirus/pathogenicity , Cardiovascular Diseases/genetics , Coronavirus Infections/genetics , Pandemics , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/genetics , Spike Glycoprotein, Coronavirus/genetics , Age Factors , Angiotensin I/therapeutic use , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , COVID-19 , Cardiovascular Diseases/complications , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/epidemiology , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Coronavirus Infections/epidemiology , Gene Expression Regulation , Host-Pathogen Interactions/genetics , Humans , Peptide Fragments/therapeutic use , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy , Pneumonia, Viral/epidemiology , Prognosis , Receptor, Angiotensin, Type 1/genetics , Receptor, Angiotensin, Type 1/metabolism , Receptors, Virus/genetics , Receptors, Virus/metabolism , SARS-CoV-2 , Sex Factors , Signal Transduction , Spike Glycoprotein, Coronavirus/metabolism
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