Abstract 14125: An in vitro Pulmonary Vascular Platform From Endothelialized Whole Lung Scaffolds

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yifan Yuan ◽  
Katherine L Leiby ◽  
Allison M Greaney ◽  
Micha Sam B Raredon ◽  
Hong Qian ◽  
...  
Keyword(s):  
Vascular Diseases ◽  
Pulmonary Vasculature ◽  
The Novel ◽  
In Vitro System ◽  
Organ Engineering ◽  
Native Lung ◽  
Whole Organ Engineering ◽  
Novel Coronavirus ◽  
Cellular Phenotypes

Introduction: The development of an in vitro system is critical to studying human diseases including the novel coronavirus disease-19 (COVID-19), and is typically centered on recapitulating native physiology. In the case of the pulmonary vasculature, the endothelium is critical for establishing the fluid-tight barrier in the alveolar compartment, and displays significant phenotypic and functional heterogeneity along vascular tree. Objective: Here, we developed an experimental platform that could mimic physiological functions and cellular phenotypes of pulmonary vasculature, during homeostatic and diseased states. Methods and Results: Lymphatic low pulmonary microvascular endothelial cells (Lymph low PMECs) were isolated from Prox1-GFP rodent lungs from regions of having low amounts of lymphatic tissue. Single-cell RNA-sequencing (scRNAseq) data revealed that these cells were becoming phenotypically homogenous over several passages while losing some markers of native differentiation during passaging. Intriguingly, after culturing in decellularized lung scaffolds, the phenotype of the lymph low PMEC changed back toward native lung endothelium. Vascular barrier function was partially restored in engineered lungs repopulated with endothelium, while small capillaries with patent lumens were appreciable. To evaluate the ability of the engineered endothelium to modulate permeability in response to exogenous stimuli, lipopolysaccharide (LPS) was introduced into repopulated lungs to simulate acute lung injury. After LPS treatment, the pro-inflammatory signal was significantly increased and the vascular barrier was severely impaired in the repopulated lung. Conclusions: Taken together, these results show a novel platform that recapitulates some pulmonary microvascular functions and phenotypes at a whole organ level. This development may help pave the way for using the whole organ engineering approach to model vascular diseases.

The Antiviral and Antimalarial Drug Repurposing in Quest of Chemotherapeutics to Combat COVID-19 Utilizing Structure-Based Molecular Docking

2020 ◽  
Vol 23 ◽  
Author(s):  
Sisir Nandi ◽  
Mohit Kumar ◽  
Mridula Saxena ◽  
Anil Kumar Saxena
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Drug Repurposing ◽  
Clinical Settings ◽  
The Novel ◽  
In Silico Docking ◽  
Biochemical Mechanisms ◽  
Novel Coronavirus ◽  
In Silico Molecular Docking

Background: The novel coronavirus disease (COVID-19) is caused by a new strain (SARS-CoV-2) erupted in 2019. Nowadays, it is a great threat that claims uncountable lives worldwide. There is no specific chemotherapeutics developed yet to combat COVID-19. Therefore, scientists have been devoted in the quest of the medicine that can cure COVID- 19. Objective: Existing antivirals such as ASC09/ritonavir, lopinavir/ritonavir with or without umifenovir in combination with antimalarial chloroquine or hydroxychloroquine have been repurposed to fight the current coronavirus epidemic. But exact biochemical mechanisms of these drugs towards COVID-19 have not been discovered to date. Method: In-silico molecular docking can predict the mode of binding to sort out the existing chemotherapeutics having a potential affinity towards inhibition of the COVID-19 target. An attempt has been made in the present work to carry out docking analyses of 34 drugs including antivirals and antimalarials to explain explicitly the mode of interactions of these ligands towards the COVID-19protease target. Results: 13 compounds having good binding affinity have been predicted towards protease binding inhibition of COVID-19. Conclusion: Our in silico docking results have been confirmed by current reports from clinical settings through the citation of suitable experimental in vitro data available in the published literature.

Synthetic and semi-synthetic drugs as promising therapeutic option for the treatment of COVID-19

2020 ◽  
Vol 20 ◽  
Author(s):  
Ekta Shirbhate ◽  
Preeti Patel ◽  
Vijay K Patel ◽  
Ravichandran Veerasamy ◽  
Prabodh C Sharma ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Antiviral Treatment ◽  
The Novel ◽  
Clinical Experiences ◽  
Synthetic Compounds ◽  
Synthetic Drugs ◽  
Global Pandemic ◽  
The World ◽  
Novel Coronavirus

: The novel coronavirus disease-19 (COVID-19), a global pandemic that emerged from Wuhan, China has today travelled all around the world, so far 216 countries or territories with 21,732,472 people infected and 770,866 deaths globally (as per WHO COVID-19 update dated August 18, 2020). Continuous efforts are being made to repurpose the existing drugs and develop vaccines for combating this infection. Despite, to date, no certified antiviral treatment or vaccine prevails. Although, few candidates have displayed their efficacy in in vitro studies and are being repurposed for COVID-19 treatment. This article summarizes synthetic and semi-synthetic compounds displaying potent activity in their clinical experiences or studies against COVID-19 and also focuses on mode of action of drugs being repositioned against COVID-19.

scholarly journals Direct antivirals working against the novel coronavirus: azithromycin (DAWn-AZITHRO), a randomized, multicenter, open-label, adaptive, proof-of-concept clinical trial of new antivirals working against SARS-CoV-2—azithromycin trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Iwein Gyselinck ◽  
◽  
Laurens Liesenborghs ◽  
Ewout Landeloos ◽  
Ann Belmans ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Standard Of Care ◽  
Ordinal Scale ◽  
Cytokine Signaling ◽  
Nasopharyngeal Swab ◽  
The Novel ◽  
Proof Of Concept ◽  
Open Label ◽  
Novel Coronavirus

Abstract Background The rapid emergence and the high disease burden of the novel coronavirus SARS-CoV-2 have created a medical need for readily available drugs that can decrease viral replication or blunt the hyperinflammatory state leading to severe COVID-19 disease. Azithromycin is a macrolide antibiotic, known for its immunomodulatory properties. It has shown antiviral effect specifically against SARS-CoV-2 in vitro and acts on cytokine signaling pathways that have been implicated in COVID-19. Methods DAWn-AZITHRO is a randomized, open-label, phase 2 proof-of-concept, multicenter clinical trial, evaluating the safety and efficacy of azithromycin for treating hospitalized patients with COVID-19. It is part of a series of trials testing promising interventions for COVID-19, running in parallel and grouped under the name DAWn-studies. Patients hospitalized on dedicated COVID wards are eligible for study inclusion when they are symptomatic (i.e., clinical or radiological signs) and have been diagnosed with COVID-19 within the last 72 h through PCR (nasopharyngeal swab or bronchoalveolar lavage) or chest CT scan showing typical features of COVID-19 and without alternate diagnosis. Patients are block-randomized (9 patients) with a 2:1 allocation to receive azithromycin plus standard of care versus standard of care alone. Standard of care is mostly supportive, but may comprise hydroxychloroquine, up to the treating physician’s discretion and depending on local policy and national health regulations. The treatment group receives azithromycin qd 500 mg during the first 5 consecutive days after inclusion. The trial will include 284 patients and recruits from 15 centers across Belgium. The primary outcome is time from admission (day 0) to life discharge or to sustained clinical improvement, defined as an improvement of two points on the WHO 7-category ordinal scale sustained for at least 3 days. Discussion The trial investigates the urgent and still unmet global need for drugs that may impact the disease course of COVID-19. It will either provide support or else justify the discouragement of the current widespread, uncontrolled use of azithromycin in patients with COVID-19. The analogous design of other parallel trials of the DAWN consortium will amplify the chance of identifying successful treatment strategies and allow comparison of treatment effects within an identical clinical context. Trial registration EU Clinical trials register EudraCT Nb 2020-001614-38. Registered on 22 April 2020

scholarly journals Characterization of the SARS-CoV-2 coronavirus X4-like accessory protein

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Olanrewaju Ayodeji Durojaye ◽  
Nkwachukwu Oziamara Okoro ◽  
Arome Solomon Odiba
Keyword(s):  
Rapid Development ◽  
Protein A ◽  
The Novel ◽  
Quality Model ◽  
A Value ◽  
Model Protein ◽  
Novel Coronavirus ◽  
Global Threat

Abstract Background The novel coronavirus SARS-CoV-2 is currently a global threat to health and economies. Therapeutics and vaccines are in rapid development; however, none of these therapeutics are considered as absolute cure, and the potential to mutate makes it necessary to find therapeutics that target a highly conserved regions of the viral structure. Results In this study, we characterized an essential but poorly understood coronavirus accessory X4 protein, a core and stable component of the SARS-CoV family. Sequence analysis shows a conserved ~ 90% identity between the SARS-CoV-2 and previously characterized X4 protein in the database. QMEAN Z score of the model protein shows a value of around 0.5, within the acceptable range 0–1. A MolProbity score of 2.96 was obtained for the model protein and indicates a good quality model. The model has Ramachandran values of φ = − 57o and ψ = − 47o for α-helices and values of φ = − 130o and ψ = + 140o for twisted sheets. Conclusions The protein data obtained from this study provides robust information for further in vitro and in vivo experiment, targeted at devising therapeutics against the virus. Phylogenetic analysis further supports previous evidence that the SARS-CoV-2 is positioned with the SL-CoVZC45, BtRs-BetaCoV/YN2018B and the RS4231 Bat SARS-like corona viruses.

scholarly journals Comparison of Four SARS-CoV-2 Neutralization Assays

Vaccines ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 13
Author(s):  
Lydia Riepler ◽  
Annika Rössler ◽  
Albert Falch ◽  
André Volland ◽  
Wegene Borena ◽  
...  
Keyword(s):  
Vesicular Stomatitis Virus ◽  
Neutralizing Antibodies ◽  
The Other ◽  
In Vitro Assays ◽  
The Novel ◽  
Effective Protection ◽  
Vaccine Candidates ◽  
Vesicular Stomatitis ◽  
Novel Coronavirus

Neutralizing antibodies are a major correlate of protection for many viruses including the novel coronavirus SARS-CoV-2. Thus, vaccine candidates should potently induce neutralizing antibodies to render effective protection from infection. A variety of in vitro assays for the detection of SARS-CoV-2 neutralizing antibodies has been described. However, validation of the different assays against each other is important to allow comparison of different studies. Here, we compared four different SARS-CoV-2 neutralization assays using the same set of patient samples. Two assays used replication competent SARS-CoV-2, a focus forming assay and a TCID50-based assay, while the other two assays used replication defective lentiviral or vesicular stomatitis virus (VSV)-based particles pseudotyped with SARS-CoV-2 spike. All assays were robust and produced highly reproducible neutralization titers. Titers of neutralizing antibodies correlated well between the different assays and with the titers of SARS-CoV-2 S-protein binding antibodies detected in an ELISA. Our study showed that commonly used SARS-CoV-2 neutralization assays are robust and that results obtained with different assays are comparable.

scholarly journals POTENTIAL THERAPIES FOR TREATMENT OF COVID-19

2020 ◽  
Vol 7 (1) ◽  
pp. 062-071
Author(s):  
Beatriz Gasser ◽  
Ricardo Andres Ramirez Uscategui
Keyword(s):  
Clinical Trials ◽  
Distress Syndrome ◽  
Multiple Organ ◽  
The Novel ◽  
Controlled Clinical Trials ◽  
Interferon Β ◽  
The World ◽  
Novel Coronavirus ◽  
Time Point

Since discovery of the novel coronavirus (SARS-CoV-2) in December of 2019, this viral pneumonia originated in Wuhan, China quickly spread around the world. This new disease, called COVID-19 can cause Acute Respiratory Distress Syndrome (ARDS) due to an uncontrolled inflammatory response like sepsis, that leads to multiple organ failure and even death. Several pharmacotherapeutics alternatives are being tested over the world, looking for most diverse drugs that might be able to fight the infection. The objective of this paper is to review the main pharmacotherapeutics techniques development, as remdesivir, chloroquine/hydroxychloroquine, lopinavir plus ritonavir, interferon-β, ivermectin, anticoagulants, convalescent plasma and vaccine, currently undergoing clinical trials in order to evaluate its effectiveness and safety to combat the COVID-19, presenting their characteristics, possible adverse effects and main scientific findings of its potential action. In conclusion, some therapies presented promising in-vitro results or in the treatment of some patients, nonetheless, multicentric blinded placebo controlled clinical trials are necessary to determine their effectiveness, safety, dosage, and best time point of treatment.

scholarly journals The IMPDH inhibitor merimepodib provided in combination with the adenosine analogue remdesivir reduces SARS-CoV-2 replication to undetectable levels in vitro

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 361
Author(s):  
Natalya Bukreyeva ◽  
Rachel A. Sattler ◽  
Emily K. Mantlo ◽  
Timothy Wanninger ◽  
John T. Manning ◽  
...  
Keyword(s):  
Disease Burden ◽  
Vero Cells ◽  
The United States ◽  
The Novel ◽  
Infectious Titer ◽  
Adenosine Analogue ◽  
Pre Treatment ◽  
Novel Coronavirus ◽  
Dose Dependent

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel coronavirus responsible for the ongoing COVID-19 pandemic, which has resulted in over 2.5 million confirmed cases and 170,000 deaths worldwide as of late April 2020. The pandemic currently presents major public health and economic burdens worldwide. No vaccines or therapeutics have been approved for use to treat COVID-19 cases in the United States despite the growing disease burden, thus creating an urgent need for effective treatments. The adenosine analogue remdesivir (REM) has recently been investigated as a potential treatment option, and has shown some activity in limiting SARS-CoV-2 replication. We previously reported that the IMPDH inhibitor merimepodib (MMPD) provides a dose-dependent suppression of SARS-CoV-2 replication in vitro. Here, we report that a 4-hour pre-treatment of Vero cells with 2.5µM MMPD reduces the infectious titer of SARS-CoV-2 more effectively than REM at the same concentration. Additionally, pre-treatment of Vero cells with both REM and MMPD in combination reduces the infectious titer of SARS-CoV-2 to values below the detectable limit of our TCID50 assay. This result was achieved with concentrations as small as 1.25 µM MMPD and 2.5 µM REM. At concentrations of each agent as low as 0.31 µM, significant reduction of viral production occurred. This study provides evidence that REM and MMPD administered in combination might be an effective treatment for COVID-19 cases.

scholarly journals Direct virucidal effect of a throat lozenge with fixed combination of cetylpyridinium chloride and benzydamine hydrochloride on SARS-CoV-2 – in vitro study

2021 ◽  
Vol 14 (3) ◽  
pp. 123-129
Author(s):  
Codrut SARAFOLEANU ◽  
◽  
Raluca ENACHE ◽  
◽  
◽  
...  
Keyword(s):  
Fixed Combination ◽  
Cetylpyridinium Chloride ◽  
In Vitro Study ◽  
Virus Concentration ◽  
The Novel ◽  
High Concentration ◽  
Virucidal Effect ◽  
Novel Coronavirus ◽  
Active Substances

Objectives. To evaluate the in vitro virucidal effect of the combination of cetylpyridinium chloride (CPC) and benzydamine hydrochloride (BH) as a throat lozenge against the novel SARS-CoV-2. Material and methods. The study evaluated the viral presence and titre in cell cultures by using SARS-CoV-2 virus incubated for 1, 5, 15 minutes, with three different concentrations of three different active substances (CPC, free BH/ CPC, BH/CPC lozenge). The titre of the virus was expressed as TCID50/ml calculated with the Spearman-Kärber method. Outcomes. The faster virucidal effect in high concentration was seen in the combination BH/CPC as throat lozenge when compared to CPC as free active substance. A reduction of the virus concentration was seen, at 15 minutes contact, in all three concentrations. Conclusions. There is a strong virucidal effect a throat lozenge with fixed combination of cetylpyridinium chloride and benzydamine hydrochloride on the novel coronavirus.

scholarly journals Sterols and Triterpenes: Antiviral     Potential Supported by In-Silico Analysis

Plants ◽  
2020 ◽  
Vol 10 (1) ◽  
pp. 41
Author(s):  
Nourhan Hisham Shady ◽  
Khayrya A. Youssif ◽  
Ahmed M. Sayed ◽  
Lassaad Belbahri ◽  
Tomasz Oszako ◽  
...  
Keyword(s):  
Active Sites ◽  
Herbal Medicines ◽  
Specific Treatment ◽  
In Silico Analysis ◽  
The Novel ◽  
Protein Targets ◽  
Drug Candidates ◽  
Novel Coronavirus ◽  
Silico Analysis

The acute respiratory syndrome caused by the novel coronavirus (SARS-CoV-2) caused severe panic all over the world. The coronavirus (COVID-19) outbreak has already brought massive human suffering and major economic disruption and unfortunately, there is no specific treatment for COVID-19 so far. Herbal medicines and purified natural products can provide a rich resource for novel antiviral drugs. Therefore, in this review, we focused on the sterols and triterpenes as potential candidates derived from natural sources with well-reported in vitro efficacy against numerous types of viruses. Moreover, we compiled from these reviewed compounds a library of 162 sterols and triterpenes that was subjected to a computer-aided virtual screening against the active sites of the recently reported SARS-CoV-2 protein targets. Interestingly, the results suggested some compounds as potential drug candidates for the development of anti-SARS-CoV-2 therapeutics.

scholarly journals A Pulmonary Vascular Model From Endothelialized Whole Organ Scaffolds

2021 ◽  
Vol 9 ◽  
Author(s):  
Yifan Yuan ◽  
Katherine L. Leiby ◽  
Allison M. Greaney ◽  
Micha Sam Brickman Raredon ◽  
Hong Qian ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Vascular Diseases ◽  
Induced Pluripotent Stem Cell ◽  
Sequencing Analysis ◽  
Conventional Culture ◽  
Bioreactor System ◽  
Whole Organ Engineering ◽  
Induced Pluripotent ◽  
The Impact

The development of an in vitro system for the study of lung vascular disease is critical to understanding human pathologies. Conventional culture systems fail to fully recapitulate native microenvironmental conditions and are typically limited in their ability to represent human pathophysiology for the study of disease and drug mechanisms. Whole organ decellularization provides a means to developing a construct that recapitulates structural, mechanical, and biological features of a complete vascular structure. Here, we developed a culture protocol to improve endothelial cell coverage in whole lung scaffolds and used single-cell RNA-sequencing analysis to explore the impact of decellularized whole lung scaffolds on endothelial phenotypes and functions in a biomimetic bioreactor system. Intriguingly, we found that the phenotype and functional signals of primary pulmonary microvascular revert back—at least partially—toward native lung endothelium. Additionally, human induced pluripotent stem cell-derived endothelium cultured in decellularized lung systems start to gain various native human endothelial phenotypes. Vascular barrier function was partially restored, while small capillaries remained patent in endothelial cell-repopulated lungs. To evaluate the ability of the engineered endothelium to modulate permeability in response to exogenous stimuli, lipopolysaccharide (LPS) was introduced into repopulated lungs to simulate acute lung injury. After LPS treatment, proinflammatory signals were significantly increased and the vascular barrier was impaired. Taken together, these results demonstrate a novel platform that recapitulates some pulmonary microvascular functions and phenotypes at a whole organ level. This development may help pave the way for using the whole organ engineering approach to model vascular diseases.

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