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1.
Front Pharmacol ; 13: 1007527, 2022.
Article in English | MEDLINE | ID: covidwho-2142207

ABSTRACT

Virus fusion process is evolutionarily conserved and provides a promising pan-viral target. Cell-cell fusion leads to syncytial formation and has implications in pathogenesis, virus spread and immune evasion. Drugs that target these processes can be developed into anti-virals. Here, we have developed sensitive, rapid, adaptable fusion reporter gene assays as models for plasma membrane and alternative fusion pathways as well as syncytial fusion in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have confirmed their specificity using neutralizing antibodies and specific protease inhibitors. The fusion report gene assays are more sensitive and unbiased than morphological fusion assay. The fusion assays can differentiate between transmembrane serine protease 2 (TMPRSS2)-dependency in TMPRSS2(+) cells and trypsin-dependency in angiotensin-converting enzyme 2 (ACE2)(+)TMPRSS2(-) cells. Moreover, we have identified putative novel fusion processes that are triggered by an acidic pH with and without trypsin. Coupled with morphological fusion criteria, we have found that syncytia formation is enhanced by TMPRSS2 or trypsin. By testing against our top drug hits previously shown to inhibit SARS-CoV-2 pseudovirus infection, we have identified several fusion inhibitors including structurally related lopsided kite-shaped molecules. Our results have important implications in the development of universal blockers and synergistic therapeutics and the small molecule inhibitors can provide important tools in elucidating the fusion process.

2.
J Biol Chem ; : 102732, 2022 Nov 21.
Article in English | MEDLINE | ID: covidwho-2122570

ABSTRACT

The emergence of new escape mutants of the SARS-CoV-2 virus has escalated its penetration among the human population and has reinstated its status as a global pandemic. Therefore, developing effective antiviral therapy against emerging SARS-CoV variants and other viruses in a short period of time becomes essential. Blocking SARS-CoV-2 entry into human host cells by disrupting the Spike glycoprotein-angiotensin-converting enzyme 2 (ACE2) interaction has already been exploited for vaccine development and monoclonal antibody therapy. Unlike the previous reports, our study used a nine-amino acid peptide from the receptor-binding motif (RBM) of the Spike (S) protein as an epitope. We report the identification of an efficacious nanobody N1.2 that blocks the entry of pseudovirus-containing SARS-CoV-2 Spike as the surface glycoprotein. Moreover, using mCherry fluorescence based reporter assay we observe a more potent neutralizing effect against both the hCoV19 (Wuhan/WIV04/2019) and the Omicron (BA.1) pseudotyped Spike virus with a bivalent version of the N1.2 nanobody. In summary, our study presents a rapid, and efficient methodology to use peptide sequences from a protein-receptor interaction interface as epitopes for screening nanobodies against potential pathogenic targets. We propose that this approach can also be widely extended to target other viruses and pathogens in the future.

3.
Journal of Infection and Public Health ; 2022.
Article in English | ScienceDirect | ID: covidwho-2120004

ABSTRACT

Background The novel coronavirus disease-2019 (COVID-19) that emerged in China, is an extremely contagious and pathogenic viral infection caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) that has sparked a global pandemic. The few and limited availability of approved therapeutic agents or vaccines is of great concern. Urgently, Remdesivir, Nirmatrelvir, Molnupiravir, and some phytochemicals including polyphenol, flavonoid, alkaloid, and triterpenoid are applied to develop as repurposing drugs against the SARS-CoV-2 invasion. Methods Firstly, this study was conducted to perform molecular docking and absorption, distribution, metabolism, excretion and toxicity (ADMET) analysis of the potential phytocompounds and repurposing drugs against three targets of SARS-CoV-2 proteins (RNA dependent RNA polymerase, RdRp, Endoribonclease, S protein of ACE2-RBD). Results The docking data illustrated Arachidonic acid, Rutin, Quercetin and Curcumin were highly bound with coronavirus polyprotein replicase and Ebolavirus envelope protein. Furthermore, anti- Ebolavirus molecule Remedesivir, anti-HIV molecule Chloroquine and Darunavir were repurposed with coronavirus polyprotein replicase as well as Ebolavirus envelope protein. The strongest binding interaction of each targets are Rutin with RdRp, Endoribonclease with Amentoflavone, and ACE2-RBD with Epigallocatechin gallate. Conclusions Taken altogether, these results shed a light on that phytocompounds have a therapeutic potential for the treatment of anti-SARS-CoV-2 may base on multi-target effects or cocktail formulation for blocking viral infection through invasion/activation, transcription/reproduction, and posttranslational cleavage to battle COVID-19 pandemic.

4.
BMC Med ; 20(1): 359, 2022 10 21.
Article in English | MEDLINE | ID: covidwho-2079420

ABSTRACT

BACKGROUND: The severe fever with thrombocytopenia syndrome disease (SFTS), caused by the novel tick-borne SFTS virus (SFTSV), was listed among the top 10 priority infectious disease by World Health Organization due to the high fatality rate of 5-30% and the lack of effective antiviral drugs and vaccines and therefore raised the urgent need to develop effective anti-SFTSV drugs to improve disease treatment. METHODS: The antiviral drugs to inhibit SFTSV infection were identified by screening the library containing 1340 FDA-approved drugs using the SFTSV infection assays in vitro. The inhibitory effect on virus entry and the process of clathrin-mediated endocytosis under different drug doses was evaluated based on infection assays by qRT-PCR to determine intracellular viral copies, by Western blot to characterize viral protein expression in cells, and by immunofluorescence assays (IFAs) to determine virus infection efficiencies. The therapeutic effect was investigated in type I interferon receptor defective A129 mice in vivo with SFTSV infection, from which lesions and infection in tissues caused by SFTSV infection were assessed by H&E staining and immunohistochemical analysis. RESULTS: Six drugs were identified as exerting inhibitory effects against SFTSV infection, of which anidulafungin, an antifungal drug of the echinocandin family, has a strong inhibitory effect on SFTSV entry. It suppresses SFTSV internalization by impairing the late endosome maturation and decreasing virus fusion with the membrane. SFTSV-infected A129 mice had relieving symptoms, reduced tissue lesions, and improved disease outcomes following anidulafungin treatment. Moreover, anidulafungin exerts an antiviral effect in inhibiting the entry of other viruses including SARS-CoV-2, SFTSV-related Guertu virus and Heartland virus, Crimean-Congo hemorrhagic fever virus, Zika virus, and Herpes simplex virus 1. CONCLUSIONS: The results demonstrated that the antifungal drug, anidulafungin, could effectively inhibit virus infection by interfering with virus entry, suggesting it may be utilized for the clinical treatment of infectious viral diseases, in addition to its FDA-approved use as an antifungal. The findings also suggested to further evaluate the anti-viral effects of echinocandins and their clinical importance for patients with infection of viruses, which may promote therapeutic strategies as well as treatments and improve outcomes pertaining to various viral and fungal diseases.


Subject(s)
Anidulafungin , Bunyaviridae Infections , Virus Diseases , Animals , Mice , Anidulafungin/pharmacology , Anidulafungin/therapeutic use , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Bunyaviridae Infections/drug therapy , Clathrin , Receptor, Interferon alpha-beta , SARS-CoV-2 , Viral Proteins , Virus Diseases/drug therapy
5.
Pharmacognosy Magazine ; 18(79):773-782, 2022.
Article in English | EMBASE | ID: covidwho-2066903

ABSTRACT

Background: Tabebuia impetiginosa is an important medicinal plant rich in lapachol, alpha-lapachone, and beta-lapachone known to possess several biological activities. Objective(s): In this study, we investigated the drug potential of lapachol, alpha-lapachone, and beta-lapachone using molecular docking, molecular dynamic (MD), and drug-likeness properties. Material(s) and Method(s): The computational study was performed using SwissADME software for the determination of the pharmacokinetic properties of the tested compounds. AutoDock Vina and Genetic Optimization for Ligand Docking (GOLD) were used for the docking analysis, and MD simulations were run using Schrodinger's Desmond Simulation. Result(s): The three compounds lapachol, alpha-lapachone, and beta-lapachone binds to cysteine (Cys)-histidine (His) catalytic dyad (Cys145 and His41) along with the other residues with, respectively, the following docking score 48.69, 47.06, and 47.79. Against viral entry receptor, human angiotensin-converting enzyme 2 (hACE-2), alpha-lapachone exhibited the highest GOLD Fitness score complex (54.82) followed by lapachol (42.53) and beta-lapachone and hACE-2 (38.74) generating several active sites in the target proteins. A 100 ns MDs simulation study revealed the stable conformation of bioactive compounds within the cavity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) of hACE-2 protein and main protease (Mpro). From the dynamic study, it was observed that lapachol was tightly bound with catalytic dyad residue Cys145 of Mpro with more than 40% time of simulation, also post-simulation MM-GBSA binding free energy (DELTAG Bind) revealed the highest energy score (-51.18 +/- 5.14 kcal/mol) among the evaluated complex. Moreover, the absorption, distribution, metabolism, and excretion (ADME) properties demonstrated that the investigated compounds passed the pharmacokinetic and drug-likeness criteria without undesirable effects. Conclusion(s): The computational study highlighted that these compounds could be highly recommended and developed as part of an effective drug against the SARS-CoV-2 virus. Copyright © 2022 Pharmacognosy Magazine.

6.
Anti-Infective Agents ; 20(4) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2065294

ABSTRACT

Background: SARS-CoV-2 infection has spread throughout the globe and has become a terrible epidemic. Researchers all around the globe are working to understand the characteristics of coronavirus and are trying to find antiviral compounds as an alternative to vaccines. Objective(s): The present study has been conceptualized to screen the various metabolites of traditional therapeutic plants that can have crucial antiviral activity against COVID-19. Method(s): Medicinal plants are rich sources of therapeutic agents of human origin. In this study, active metabolites from plants such as O. sanctum, C. longa, A. indica, Z. officinale, A. paniculata, G. glabra, A. sativum, P. guajava, V. negundo and S. aromaticum have been studied. This study aims to control COVID-19, either by interfering with the Cysteine-like protease (3CLpro) component of COVID-19 or by blocking viral entry via the human angiotensin-converting enzyme 2 (ACE 2) receptor. The molecular docking of forty plant metabolites was studied with the 3Clpro component and ACE 2 receptors. In addition to this, the binding capacity of these two targets was also compared with hydroxychloroquine used for its treatment. Result(s): The results reveal that Glycyrrhizin binds to 3CLpro in a highly stable manner with the lowest binding energy. Glabridin, beta-sitosterol, beta-Caryophyllene, alpha-Curcumene, and Apigenin, among others, have shown effective interactions with both ACE 2 and 3CLpro. The study reveals the ability of more than 20 plant-based compounds against the COVID-19 infection cycle, which are more effective than hydroxychloroquine. Conclusion(s): Medicinal plant-based therapeutic compounds might provide quickly, sensitive, precise, and cost-effective alternative therapies. To reduce adverse effects, many pharmacological characteristics of medicinal plant agents should be adjusted. Copyright © 2022 Bentham Science Publishers.

7.
Chest ; 162(4):A1310, 2022.
Article in English | EMBASE | ID: covidwho-2060803

ABSTRACT

SESSION TITLE: Unique Inflammatory and Autoimmune Complications of COVID-19 Infections SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Viral infections can induce an immune cascade which may incite varied autoimmune disease to take action. One such disease is dermatomyositis, a rare inflammatory disease with multisystemic involvement. As we enter the post pandemic era, several unique complications related to COVID-19 are now surfacing. Here we present a case of a 57-year-old female who developed dermatomyositis after recent Covid-19 infection. CASE PRESENTATION: Patient is a 57-year-old female who presented to our pulmonary clinic with complaints of cough and shortness of breath (SOB). Patient reported feeling ill since contracting COVID-19 in November 2020. Two months after being diagnosed with COVID-19 she started to experience generalized muscle and joint pain;she underwent extensive rheumatological workup which was consistent with Sjogren disease for which she was started on hydroxychloroquine. A month after initiation of medication she started to experience worsening cough and SOB and underwent pulmonary function testing (PFT) in our clinic which showed evidence of restrictive lung disease. Chest CT was consistent with interstitial changes, therefore a diagnosis of ILD (interstitial lung disease) due to connective tissue disorder was made. Further assessment revealed positive CPK and anti-Jo1 antibodies indicative of dermatomyositis as a cause of her ILD. She was started on oral steroids which helped improve her symptoms. DISCUSSION: Several viruses including EBV, Hepatitis C, Rubella, HTLV-1 and Parvovirus have been associated with development of autoimmune diseases. Viral infections, like COVID-19 have shown to trigger an intense immune response which in turn may lead to autoimmune activity against host antigen. SARS-CoV2 has been found to enter muscle cells through ACE-2 receptors, allowing for transfer of genetic material and skeletal muscle damage. Another proposed mechanism of COVID induced myopathy has been T-cell clonal expansion by the virus up regulating TLR4 receptors increasing expression of ACE2, therefore facilitating entry of viruses leading to further inflammation. Identification of very specific T cell receptor epitopes for SARS-COv2 in patients with dermatomyositis has suggested COVID-19 as a trigger for CD8-T cells which leads to dermatomyositis in these patients. Autoimmune reactions occur from varying mechanisms like epitope spreading and bystander activation to molecular mimicry triggered by viral infections. CONCLUSIONS: SARS-COv2 presented with several challenges in the field of medicine. As we enter the post COVID period in medicine, we will continue to face several challenges proposed by the inflammatory surge caused by this disease. It is therefore important clinicians recognize and report these rare cases to increase awareness regarding several post covid diseases. Reference #1: HUSSEIN, H. M.;RAHAL, E. A. The role of viral infections in the development of autoimmune diseases. Critical Reviews in Microbiology, [s. l.], v. 45, n. 4, p. 394–412, 2019. DOI 10.1080/1040841X.2019.1614904. Disponível em: https://search-ebscohost-com.proxy.lib.wayne.edu/login.aspx?direct=true&db=a9h&AN=138199390&site=ehost-live&scope=site. Acesso em: 4 abr. 2022. DISCLOSURES: No relevant relationships by Kevser Akyuz No relevant relationships by Ranim Chamseddin No relevant relationships by Padmini Giri No relevant relationships by verisha khanam No relevant relationships by Emad Shehada No relevant relationships by Abdullah Yesilyaprak

8.
Chest ; 162(4):A1040-A1041, 2022.
Article in English | EMBASE | ID: covidwho-2060759

ABSTRACT

SESSION TITLE: COVID-19 Case Report Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Malignant hyperthermia (MH) is a hypermetabolic crisis where an increase in carbon dioxide is seen despite an increased minute ventilation with a proposed mechanism as a disturbance in calcium homeostasis. Commonly seen in volatile anesthetic agents and depolarizing neuromuscular blockers, rarely with nondepolarizing agents. There has been one reported case of cisatracurium-induced MH in the setting of ARDS. There have been two cases reported of nondepolarizing neuromuscular agents causing MH in the setting of COVID-19. CASE PRESENTATION: A 34-year-old man with severe COVID-19 complicated by ARDS on ventilator day 16, due to refractory fevers, ventilatory dyssynchrony, high minute ventilation and auto-PEEP phenomena, the decision was made to attempt neuromuscular paralysis. After one dose of cisatracurium, the patient became hyperthermic and end-tidal carbon-dioxide increased from 58-98 with inability to oxygenate. The patient developed high peak pressures, bedside ultrasound revealed no evidence of pneumothorax also confirmed with chest x-ray. The patient then received a dose of dantrolene with end-tidal improving to 60 and tachycardia also resolved. A creatinine kinase level drawn was elevated at 571. DISCUSSION: A proposed mechanism of MH is calcium release from sarcoplasmic reticulum, a mutation in skeletal muscle ryanodine receptor calcium release channels that can release IL-6 when activated leading to excessive muscular contraction. Proinflammatory cytokine IL-6, dantrolene may block IL-6 release which results in its therapeutic effect in the treatment of MH. IL-6 has been used to predict deterioration from COVID-19. Dantrolene in this sense has been proposed as a potential therapeutic agent against COVID-19, inhibiting intracellular calcium influx thus preventing the pathological feedback of viral entry into cells via endocytosis, as this is a calcium dependent process. Given the possible link between IL-6 release, calcium and MH, SARS-CoV-2 viral entry into cells may place patients at higher risk of MH. Patients with COVID-19 may be at higher risk of MH, even in rare agents such as non-depolarizing agents as seen in this case. Awareness of this potentially increased complication from these agents in those patients with COVID-19 is key as we continue in the ongoing global pandemic. CONCLUSIONS: Given the possible link between IL-6 release, calcium and MH, SARS-CoV-2 viral entry into cells may place patients at higher risk of MH. Patients with COVID-19 may be at higher risk of malignant hyperthermia, even in rare agents such as non-depolarizing agents as seen in this case. Awareness of this potentially increased complication from these agents in those patients with COVID-19 is key as we continue in the ongoing global pandemic. Reference #1: Sathyanarayanan SP, Hamza M, Hamid K, Groskreutz D. Cisatracurium-Associated Malignant Hyperthermia During Severe Sars-CoV-2 Infection. Am J Ther. 2021 Aug 10;28(5):e590-e591. doi: 10.1097/MJT.0000000000001437. PMID: 34387563;PMCID: PMC8415506. Reference #2: Chiba N, Matsuzaki M, Mawatari T, Mizuochi M, Sakurai A, Kinoshita K. Beneficial effects of dantrolene in the treatment of rhabdomyolysis as a potential late complication associated with COVID-19: a case report. Eur J Med Res. 2021 Feb 8;26(1):18. doi: 10.1186/s40001-021-00489-8. PMID: 33557936;PMCID: PMC7868892. Reference #3: Han H, Ma Q, Li C, Liu R, Zhao L, Wang W, Zhang P, Liu X, Gao G, Liu F, Jiang Y, Cheng X, Zhu C, Xia Y. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect. 2020 Dec;9(1):1123-1130. doi: 10.1080/22221751.2020.1770129. PMID: 32475230;PMCID: PMC7473317. DISCLOSURES: No relevant relationships by Hira Bakhtiar No relevant relationships by Timothy DAmico no disclosure on file for Sarah Margolskee;No relevant relationships by Carlos Merino No relevant relationships by Joanna Moore

9.
Chest ; 162(4):A587, 2022.
Article in English | EMBASE | ID: covidwho-2060639

ABSTRACT

SESSION TITLE: Management of COVID-19-Induced Complications SESSION TYPE: Rapid Fire Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 1:45 pm INTRODUCTION: Myalgias are one of the most common manifestations of a COVID infection. Myositis is much less reported with the spectrum of presentation ranging from asymptomatic elevation of creatinine kinase (CK) to rhabdomyolysis. Further understanding is required to formulate evidence based protocols for management and prognostication. CASE PRESENTATION: A 25-year-old male smoker, unvaccinated for COVID presented to the hospital with fever, weakness and myalgias and tested positive for COVID. Examination showed mild tenderness in the proximal muscles of the lower extremities. Labs were significant for metabolic acidosis, hypocalcemia, hyperkalemia, acute kidney injury, AST 6178, ALT 1340, CK > 36000 and CPK > 60000 and gross hematuria. Electrolyte abnormalities were corrected and he received aggressive hydration with intravenous fluids containing bicarbonate. Oxygen requirements increased and he received dexamethasone and Baricitinib for COVID. His creatinine continued to increase despite downtrending transaminases and CK. Ultrasound liver was normal. He developed bilateral pleural effusions and mild ascites suspected secondary to volume overload in the setting of acute renal failure. Hemodialysis was initiated and he received a total of 6 sessions of hemodialysis over the next week. Creatinine, BUN and GFR significantly improved. AntiJo1 Ab ordered to rule out polymyositis was negative. Transaminitis and raised CK levels downtrended alongside the COVID inflammatory markers and oxygen requirements as the patient was weaned to room air. DISCUSSION: The spectrum of COVID myositis reported thus far covers asymptomatic elevation of muscle enzymes, myasthenia, paraspinal myositis, dermatomyositis and rhabdomyolysis (1). The pathophysiology of COVID myositis has been hypothesized to be through ACE2 receptor mediated viral entry into muscle fibers leading to activation of innate and adaptive immunity. Other proposed mechanisms include the release of inflammatory cytokines and molecular mimicry with cross reaction of the antiviral antibodies. Myositis was most reported most commonly among males aged 33–87 (1). Symptoms when present include fevers, cough, shortness of breath, myalgias and proximal, lower limb–dominant, acute, and symmetric weakness. Peak CK values as high as 33,000 U/L have been reported (2). In general, patients diagnosed with rhabdomyolysis appear to have negative myositis-specific autoantibodies and higher CK levels than those without, highlighting the need for close monitoring of CK levels. Rhabdomyolysis associated fatality was reported to be as high as 45% (4 of 9 reported) over a short follow-up duration (1). Our case documents a recovery period in days-weeks with hydration and hemodialysis (3). CONCLUSIONS: Areas for exploration include factors predisposing patients to rhabdomyolysis, utility of checking enzyme levels and impact of vaccination on disease severity. Reference #1: Saud A, Naveen R, Aggarwal R, Gupta L. COVID-19 and Myositis: What We Know So Far. Curr Rheumatol Rep. 2021 Jul 3;23(8):63. doi: 10.1007/s11926-021-01023-9. PMID: 34216297;PMCID: PMC8254439. Reference #2: Husain R, Corcuera-Solano I, Dayan E, Jacobi AH, Huang M. Rhabdomyolysis as a manifestation of a severe case of COVID-19: A case report. Radiol Case Rep. 2020 Jul 7;15(9):1633-1637. doi: 10.1016/j.radcr.2020.07.003. PMID: 32690987;PMCID: PMC7340044. Reference #3: Byler J, Harrison R, Fell LL. Rhabdomyolysis Following Recovery from Severe COVID-19: A Case Report. Am J Case Rep. 2021 May 8;22:e931616. doi: 10.12659/AJCR.931616. PMID: 33963170;PMCID: PMC8127859. DISCLOSURES: No relevant relationships by Asim Amjad No relevant relationships by Sarasija Natarajan No relevant relationships by Pius Ochieng No relevant relationships by Yamini Patel

10.
Chest ; 162(4):A156, 2022.
Article in English | EMBASE | ID: covidwho-2060541

ABSTRACT

SESSION TITLE: Infections In and Around the Heart Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Due to the novelty of COVID-19 virus, complications of this severe respiratory infection are continually emerging. The inflammatory response to the virus carries a high mortality rate and can lead to a variety of cardiothoracic complications such as acute coronary syndrome, thromboembolism, and heart failure [1]. Here, we present a case of a young female who suffered cardiac tamponade (CT) from a pericardial effusion (PEEF) attributed to COVID-19 infection, which has only been described a handful of times in the literature. CASE PRESENTATION: A 33-year-old female with a history of Down syndrome and morbid obesity presented with worsening dyspnea and fever for one week. Her initial oxygen saturation was 50% on room air, and bilevel noninvasive ventilatory support was initiated. Her viral PCR was positive for COVID-19. A computed tomography angiogram of the chest revealed small bilateral pulmonary emboli, diffuse ground-glass consolidations, and small bilateral pleural effusions. Her respiratory status continued to decompensate and she was placed on mechanical ventilation. She became hypotensive requiring vasopressor support. The following morning, an echocardiogram (TTE) revealed an ejection fraction of 40-45% and a new PEEF with early right ventricular diastolic collapse consistent with CT physiology. She underwent emergent pericardiocentesis, and 220 mL of bloody fluid was drained. PEEF studies revealed a glucose level of 186 mg/dL, LDH of 1380 U/L, and protein of 3.0 g/dL. Total nucleated count was 16,545/uL with 68% neutrophils. Gram stain showed a few white blood cells without organisms, and final bacterial, fungal, and acid-fast cultures were negative. A pericardial drain was left in place, but the procedure was complicated by a pneumothorax and a chest tube was placed. A follow-up TTE the next day revealed improvement of the PEEF without signs of CT. A repeat chest x-ray showed resolution of the pneumothorax. Unfortunately, the patient’s oxygenation and hemodynamic status continued to worsen. She eventually suffered cardiac arrest with pulseless electrical activity and succumbed to her illness. DISCUSSION: New knowledge regarding complications of COVID-19 infection is continually emerging. According to a February 2022 systematic review, only 30 cases of severe PEEFs with CT secondary to COVID-19 have been recorded. The mechanism by which PEEFs form is unclear. It is proposed that the entry of the virus into inflammatory cells causes a release of cytokines such as TNF-alpha, IL-1, IL-6, and IL-8. This resulting cytokine storm allows rapid inflammation and infiltration of fluid into the pericardial sac [1]. CONCLUSIONS: In a decompensated patient with COVID-19, a stat TTE should be obtained to rule out PEEF. Physicians must be cognizant of this uncommon yet highly fatal complication in unstable COVID-19 patients, as cardiac tamponade is a potentially reversible cause of cardiac arrest. Reference #1: Kermani-Alghoraishi, M., Pouramini, A., Kafi, F., & Khosravi, A. (2022). Coronavirus Disease 2019 (COVID-19) and Severe Pericardial Effusion: From Pathogenesis to Management: A Case Report Based Systematic Review. Current problems in cardiology, 47(2), 100933. https://doi.org/10.1016/j.cpcardiol.2021.100933 DISCLOSURES: No relevant relationships by Amanda Cecchini No relevant relationships by Arthur Cecchini No relevant relationships by Kevin Cornwell No relevant relationships by Krupa Solanki

11.
Journal of Cellular Neuroscience and Oxidative Stress ; 14(2):17, 2022.
Article in English | EMBASE | ID: covidwho-2057541

ABSTRACT

Living systems have hundreds of ion channels on their surfaces. The TRP protein family defined in Drosophila is one of the channels providing ion passage and is present in living systems from simple organisms to complex. TRP channels have various roles in sensory systems and are located in almost all cells. TRP cation channels of mammals consist of seven subfamilies and each of them has their own structure, location etc. (Clapham, 2003). Since they play a role in sensory transmission, sciencists think that they could be potential targets for relieving the symptoms of various diseases (Miller, 2006). COVID-19 disease caused by the SARS-Cov-2 virus occurs with symptoms such as headache, muscle pain, respiratory and digestive problems, and loss of taste and smell. TRP channels have been targeted in some approaches to reduce these symptoms. In some studies that blocked TRP channels, the symptoms were observed to disappear or to decrease significantly (Fernandes et al., 2012). The virus requires angiotensin converting enzyme 2 and transmembrane protease serine 2 proteins to enter host cells. These processes are mediated by endocytosis and by Ca+ flow. In this context, it has been observed that the blocking of TRP channels hinders the entry of the virus into the host. The aim of this review is to examine the severe symptoms, the potential roles of TRP ion channels in the spread and progression processes of the COVID-19 pandemic, which led to a worldwide crisis, as well as their therapeutic approaches.

12.
J Biol Chem ; 298(11): 102500, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2041895

ABSTRACT

Coronavirus disease represents a real threat to the global population, and understanding the biological features of the causative virus, that is, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is imperative for mitigating this threat. Analyses of proteins such as primary receptors and coreceptors (cofactors), which are involved in the entry of SARS-CoV-2 into host cells, will provide important clues to help control the virus. Here, we identified host cell membrane protein candidates present in proximity to the attachment sites of SARS-CoV-2 spike proteins, using proximity labeling and proteomic analysis. The identified proteins represent key candidate factors that may be required for viral entry. We found SARS-CoV-2 host protein DPP4, cell adhesion protein Cadherin 17, and glycoprotein CD133 colocalized with cell membrane-bound SARS-CoV-2 spike proteins in Caco-2 cells and thus showed potential as candidate factors. Additionally, our analysis of the experimental infection of HEK293T cells with a SARS-CoV-2 pseudovirus indicated a 2-fold enhanced infectivity in the CD133-ACE2-coexpressing HEK293T cells compared to that in HEK293T cells expressing ACE-2 alone. The information and resources regarding these coreceptor labeling and analysis techniques could be utilized for the development of antiviral agents against SARS-CoV-2 and other emerging viruses.


Subject(s)
COVID-19 , Membrane Proteins , Spike Glycoprotein, Coronavirus , Virus Attachment , Humans , Angiotensin-Converting Enzyme 2 , Caco-2 Cells , HEK293 Cells , Membrane Proteins/metabolism , Protein Binding , Proteomics , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/metabolism , Virus Internalization , Receptors, Virus/metabolism
13.
Proc Natl Acad Sci U S A ; 119(38): e2209514119, 2022 09 20.
Article in English | MEDLINE | ID: covidwho-2017036

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) cell entry starts with membrane attachment and ends with spike (S) protein-catalyzed membrane fusion depending on two cleavage steps, namely, one usually by furin in producing cells and the second by TMPRSS2 on target cells. Endosomal cathepsins can carry out both. Using real-time three-dimensional single-virion tracking, we show that fusion and genome penetration require virion exposure to an acidic milieu of pH 6.2 to 6.8, even when furin and TMPRSS2 cleavages have occurred. We detect the sequential steps of S1-fragment dissociation, fusion, and content release from the cell surface in TMPRRS2-overexpressing cells only when exposed to acidic pH. We define a key role of an acidic environment for successful infection, found in endosomal compartments and at the surface of TMPRSS2-expressing cells in the acidic milieu of the nasal cavity.


Subject(s)
COVID-19 , Nasal Cavity , SARS-CoV-2 , Serine Endopeptidases , Virus Internalization , COVID-19/virology , Furin/genetics , Furin/metabolism , Humans , Hydrogen-Ion Concentration , Nasal Cavity/chemistry , Nasal Cavity/virology , SARS-CoV-2/physiology , Serine Endopeptidases/metabolism , Spike Glycoprotein, Coronavirus/metabolism
14.
Viruses ; 14(8)2022 08 08.
Article in English | MEDLINE | ID: covidwho-2010305

ABSTRACT

The pandemics caused by emerging viruses such as severe acute respiratory syndrome coronavirus 2 result in severe disruptions to public health. Vaccines and antibody drugs play essential roles in the control and prevention of emerging infectious diseases. However, in contrast with the neutralizing antibodies (NAbs), sub- or non-NAbs may facilitate the virus to enter the cells and enhance viral infection, which is termed antibody-dependent enhancement (ADE). The ADE of most virus infections is mediated by the Fc receptors (FcRs) expressed on the myeloid cells, while others are developed by other mechanisms, such as complement receptor-mediated ADE. In this review, we comprehensively analyzed the characteristics of the viruses inducing FcRs-mediated ADE and the new molecular mechanisms of ADE involved in the virus entry, immune response, and transcription modulation, which will provide insights into viral pathogenicity and the development of safer vaccines and effective antibody drugs against the emerging viruses inducing ADE.


Subject(s)
COVID-19 , Virus Diseases , Viruses , Antibodies, Neutralizing , Antibodies, Viral , Antibody-Dependent Enhancement , Humans , Receptors, Fc , Virus Diseases/prevention & control
15.
Russian Archives of Internal Medicine ; 12(4):245-253, 2022.
Article in Russian | EMBASE | ID: covidwho-2006639

ABSTRACT

The safety of proton pump inhibitors (PPIs) use in coronavirus infection (COVID-19) is not well understood. PPIs are potent suppressors of gastric secretion and become one of the ten most widely used drugs in the world. They are expected to influence virus susceptibility, severity, and outcomes in patients diagnosed with COVID-19. This concern is based on their mechanism of action — suppression of gastric acidity, which is considered the first line of defense against infections. Taken together, the results of most studies and meta-analyses support that PPIs use has been associated with increased risk of COVID-19 and severe outcomes. However, taking into account all potential risk factors for disease severity seems impossible in the real world in the context of COVID-19, so conclusions about causal relationships between PPI use and COVID-19 should be treated with great caution. An additional interesting point about the use of PPIs in the pandemic is that it reduced absorption of certain vitamins. On the other hand, several studies have appeared in the literature regarding the protective therapeutic effects of PPIs. There is growing evidence of an immunomodulatory and antifibrotic role of PPIs that could be used in the treatment of COVID-19. In addition, their ability to alkalize the contents of endosomes and lysosomes serves as an obstacle to the penetration of the virus into host cells. This review analyzes the possible effects of PPIs in patients with COVID-19.

16.
J Virol ; 96(17): e0114022, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-2001778

ABSTRACT

The SARS-CoV-2 Omicron variants were first detected in November 2021, and several Omicron lineages (BA.1, BA.2, BA.3, BA.4, and BA.5) have since rapidly emerged. Studies characterizing the mechanisms of Omicron variant infection and sensitivity to neutralizing antibodies induced upon vaccination are ongoing by several groups. In the present study, we used pseudoviruses to show that the transmembrane serine protease 2 (TMPRSS2) enhances infection of BA.1, BA.1.1, BA.2, and BA.3 Omicron variants to a lesser extent than ancestral D614G. We further show that Omicron variants have higher sensitivity to inhibition by soluble angiotensin-converting enzyme 2 (ACE2) and the endosomal inhibitor chloroquine compared to D614G. The Omicron variants also more efficiently used ACE2 receptors from 9 out of 10 animal species tested, and unlike the D614G variant, used mouse ACE2 due to the Q493R and Q498R spike substitutions. Finally, neutralization of the Omicron variants by antibodies induced by three doses of Pfizer/BNT162b2 mRNA vaccine was 7- to 8-fold less potent than the D614G. These results provide insights into the transmissibility and immune evasion capacity of the emerging Omicron variants to curb their ongoing spread. IMPORTANCE The ongoing emergence of SARS-CoV-2 Omicron variants with an extensive number of spike mutations poses a significant public health and zoonotic concern due to enhanced transmission fitness and escape from neutralizing antibodies. We studied three Omicron lineage variants (BA.1, BA.2, and BA.3) and found that transmembrane serine protease 2 has less influence on Omicron entry into cells than on D614G, and Omicron exhibits greater sensitivity to endosomal entry inhibition compared to D614G. In addition, Omicron displays more efficient usage of diverse animal species ACE2 receptors than D614G. Furthermore, due to Q493R/Q498R substitutions in spike, Omicron, but not D614G, can use the mouse ACE2 receptor. Finally, three doses of Pfizer/BNT162b2 mRNA vaccination elicit high neutralization titers against Omicron variants, although the neutralization titers are still 7- to 8-fold lower those that against D614G. These results may give insights into the transmissibility and immune evasion capacity of the emerging Omicron variants to curb their ongoing spread.


Subject(s)
Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing , COVID-19 , Immune Evasion , SARS-CoV-2 , Virus Internalization , Angiotensin-Converting Enzyme 2/chemistry , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/immunology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , COVID-19/immunology , COVID-19/virology , Humans , Immune Evasion/immunology , Mice , SARS-CoV-2/chemistry , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Species Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolism
17.
J Virol ; 96(17): e0081422, 2022 09 14.
Article in English | MEDLINE | ID: covidwho-2001773

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted between humans and minks, and some mutations in the spike (S) protein, especially in the receptor-binding domain (RBD), have been identified in mink-derived viruses. Here, we examined binding of the mink angiotensin-converting enzyme 2 (ACE2) receptor to mink-derived and important human-originating variants, and we demonstrated that most of the RBD variants increased the binding affinities to mink ACE2 (mkACE2). Cryo-electron microscopy structures of the mkACE2-RBD Y453F (with a Y-to-F change at position 453) and mkACE2-RBD F486L complexes helped identify the key residues that facilitate changes in mkACE2 binding affinity. Additionally, the data indicated that the Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and human vaccinated sera efficiently prevented infection of human cells by pseudoviruses expressing Y453F, F486L, or N501T RBD. Our findings provide an important molecular mechanism for the rapid adaptation of SARS-CoV-2 in minks and highlight the potential influence of the main mink-originating variants for humans. IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a broad range of hosts. Mink-derived SARS-CoV-2 can transmit back to humans. There is an urgent need to understand the binding mechanism of mink-derived SARS-CoV-2 variants to mink receptor. In this study, we identified all mutations in the receptor-binding domain (RBD) of spike (S) protein from mink-derived SARS-CoV-2, and we demonstrated the enhanced binding affinity of mink angiotensin-converting enzyme 2 (ACE2) to most of the mink-derived RBD variants as well as important human-originating RBD variants. Cryo-electron microscopy structures revealed that the Y453F and F486L mutations enhanced the binding forces in the interaction interface. In addition, Y453F and F486L mutations reduced the binding affinities to some human monoclonal antibodies, and the SARS-CoV-2 pseudoviruses with Y453F, F486L, or N501T mutations were neutralized by human vaccinated sera. Therefore, our results provide valuable information for understanding the cross-species transmission mechanism of SARS-CoV-2.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19/veterinary , Mink , Spike Glycoprotein, Coronavirus/metabolism , Angiotensin-Converting Enzyme 2/genetics , Animals , Antibodies, Monoclonal/metabolism , COVID-19/virology , Cryoelectron Microscopy , Humans , Mutation , Peptidyl-Dipeptidase A/metabolism , Protein Binding , SARS-CoV-2/genetics
18.
Cancer Research ; 82(12), 2022.
Article in English | EMBASE | ID: covidwho-1986495

ABSTRACT

As of November 2021, there were 21 million confirmed active cases of COVID-19, including 77,016 patients in serious or critical condition (virusncov.com). However, there are no effective oral drugs for the treatment of severe COVID 19 patients. We here discuss the mechanism of action for Proxalutaminde to treat mild, moderate and severe COVID-19 Patients. Cellular entry and infection of SARS-CoV-2 virus are mediated by two key proteins in host cells, angiotensin converting enzyme 2 (ACE2), a host transmembrane protein, providing the binding sites for SARS-CoV-2 on the host cell surface, and transmembrane protease serine 2 protein (TMPRSS2), priming the S protein of SARS-Cov-2 to facilitate the viral entry into the host cells. Both ACE2 and TMPRSS2 proteins are regulated by androgen receptor (AR) signaling. Previously, Proxalutamide has been reported to downregulate the expression of ACE2 and TMPRSS2 in cells derived from prostate, lung cancer and normal lung epithelial cells. In this study, we demonstrate that Proxalutamide inhibited the infection of SARS-COV-2 wild type, alpha and delta variants, with IC50s of 69, 48 and 39 nM, respectively. Moreover, Proxalutamide reduced SARS-COV-2 viral load in outpatients with COVID-19 (82% viral RT-PCR negative rate in active group vs. 31% in placebo group after treatment for 7 days (p-value<0.0001). Severe COVID-19 disease leads to cytokine storm resulting in pulmonary inflammation and extensive damage in lung and other organs. Anti-inflammatory drugs, including Baricitinib and dexamethasone, have shown limited clinical benefit for hospitalized COVID-19 patients. Therefore, more effective drugs are in urgent need for patients suffering from severe COVID-19. Recently, Proxalutamide has been reported to reduce the mortality rate (HR=0.16) and lung injury (by 57%, active drug vs placebo groups) in hospitalized patients with COVID-19 in an IIT phase III study. We presented here the mechanism of action of Proxalutamide for targeting cytokine storm in severe COVID-19 patients. Proxalutamide was demonstrated to activate nuclear factor erythroid 2-related factor 2 (Nrf2) in macrophages, which stimulates the antioxidant response element (ARE) for reducing cytokine storm-induced organ damage in COVID-19. In addition, Proxalutamide inhibited TNF alpha and IL-6 expression and blocked INF gamma signaling by downregulating STAT1 expression in immune cells. Importantly, Proxalutamide reduced inflammatory cells in lungs in a Poly (I:C), pseudoviral induced-lung injury animal models. Further, Proxalutamide decreased C-reactive protein, D-Dimer and improved lymphocyte count, biomarkers for COVID-19 progression in clinical studies. Together, these results provide a strong rationale for the treatment of severe COVID-19 patients with Proxalutamide.

19.
EJVES Vascular Forum ; 54:e11-e12, 2022.
Article in English | EMBASE | ID: covidwho-1982964

ABSTRACT

Introduction: The lack of a history of the course of a new coronavirus infection and the lack of data from randomised trials makes it difficult to choose the right treatment tactics and prescribe adequate prophylaxis in patients who have suffered from COVID-19. Comorbid patients with cardiovascular diseases and endothelial dysfunction have a high risk of a severe course of COVID-19 and subsequent thrombotic complications, which manifest clinically as cardiomyopathy;venous thrombo-embolism (deep vein thrombosis and pulmonary embolism);pulmonary thrombosis in situ;stroke;arterial thrombangiitis;rarely, arterial peripheral thrombosis and microvascular thrombosis, in the lungs, liver, kidneys, brain, etc.;and mild disseminated intravascular coagulation syndrome. The role of endothelial dysfunction in the development of severe complications is underestimated. In the pathogenesis of COVID-19, the defeat of the microcirculatory bed plays a crucial role. The SARS-CoV-2 virus causes associated endotheliitis damage to the endothelium due to virus entry and cytokine storm. Endotheliitis leads to the release of tissue factor, which leads to the formation of an excess of thrombin and fibrin;the body tries to cover the virus with these and prevent its spread, which entails negative side effect such as thrombosis Methods: Sixty-six patients who had COVID-19 were examined (42 women and 24 men;mean age 48 years [range 20 – 80 years]). Patients complained of a feeling of paraesthesia, mainly in the lower extremities, a feeling of heaviness, stiffness in the popliteal region, an increased vascular pattern on the entire surface of the skin, a burning sensation in all vessels, and a feeling of weakness. Ultrasound colour duplex scanning showed no signs of thrombosis in the large vessels. Using a high frequency ultrasound Doppler and a 25 MHz sensor, the nailbed of the first finger of the upper limb was examined. The microcirculatory images were analysed by the shape and spectrum of the curves. Twenty patients received prophylaxis with rivaroxaban 10 mg daily (group 1) and 46 patients did not (group 2). The control examination was carried out four weeks after the start of therapy: sulodexide one capsule twice daily. The coagulogram parameters were also studied. Results: A depletion in spectral characteristics was seen in patients after COVID-19 disease, in comparison to microcirculatory images recorded in healthy individuals. Predominantly, the red part of the spectrum was recorded in patients after COVID-19, the lighter part of the spectrum was not recorded. Group 1 patients had higher amplitude parameters than group 2, but they also registered a depletion in spectral characteristics. Soluble fibrin monomer complexes were increased 4 – 5 times, D-dimer 2 – 2.5 times, and antithrombin III 1.5 times. The international normalised ratio, activated partial thromboplastin time, fibrinogen, prothrombin according to Quick, prothrombin time, clotting time, and bleeding time were within the reference intervals both before and after treatment. Upon repeat examination four weeks after the course of sulodexide therapy, the spectral characteristics were normalised, and the coagulogram parameters were also normalised. Conclusion: The red part of the spectrum, according to the Doppler criteria, corresponds to the fastest particles moving in the middle of the stream. The lighter part of the spectrum corresponds to particles moving more slowly. The reduction in spectral characteristics in patients after COVID-19 disease corresponds to parietal stasis and readiness for thrombosis, which was confirmed by the coagulogram data. Examination of the nailbed using high frequency ultrasound Doppler in patients who have COVID-19 allows the identification of stasis of the parietal blood flow, which corresponds to a prethrombotic state. The prescription of sulodexide allows for an improvement in the condition of patients and normalisation of microcirculation indicators

20.
FEBS Open Bio ; 12:66, 2022.
Article in English | EMBASE | ID: covidwho-1976674

ABSTRACT

Since its outbreak, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) caused one of the most severe pandemics in recent history and had enormous effects on the lives of millions of people worldwide. Peptidases, both viral and host, have been described as critical enzymes in mechanisms underlying SARS-CoV-2 infection and replication. Among host peptidases, the involvement in activation of viral glycoproteins and processing of the SARS-CoV spike protein has been described for endosomal/lysosomal cysteine peptidases cathepsins B and L, which therefore represent promising targets for development of effective drugs for treatment of COVID-19. To date, a large number of cathepsin B and L inhibitors have been identified and evaluated for treatment of various pathological processes. In this study, we have evaluated well-established known potent selective and reversible cathepsin B inhibitors for their potential to act against SARS-CoV-2. Cathepsin B inhibitors showed significant activity in preventing viral entry and replication of SARS-CoV-2. Next, we observed that antiviral activity of compounds was dependent on the cell type and correlated well with the intracellular amount of the targeted cathepsin. Taken together, we have demonstrated the important role of host cysteine peptidase cathepsin B during SARS-CoV-2 infection and identified its inhibitors as potential new therapeutic agents for treatment of SARS-CoV-2 infection.

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