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1.
Stem Cell Reports ; 17(2): 307-320, 2022 02 08.
Article in English | MEDLINE | ID: covidwho-1712991

ABSTRACT

Neurological complications are common in COVID-19. Although SARS-CoV-2 has been detected in patients' brain tissues, its entry routes and resulting consequences are not well understood. Here, we show a pronounced upregulation of interferon signaling pathways of the neurovascular unit in fatal COVID-19. By investigating the susceptibility of human induced pluripotent stem cell (hiPSC)-derived brain capillary endothelial-like cells (BCECs) to SARS-CoV-2 infection, we found that BCECs were infected and recapitulated transcriptional changes detected in vivo. While BCECs were not compromised in their paracellular tightness, we found SARS-CoV-2 in the basolateral compartment in transwell assays after apical infection, suggesting active replication and transcellular transport of virus across the blood-brain barrier (BBB) in vitro. Moreover, entry of SARS-CoV-2 into BCECs could be reduced by anti-spike-, anti-angiotensin-converting enzyme 2 (ACE2)-, and anti-neuropilin-1 (NRP1)-specific antibodies or the transmembrane protease serine subtype 2 (TMPRSS2) inhibitor nafamostat. Together, our data provide strong support for SARS-CoV-2 brain entry across the BBB resulting in increased interferon signaling.


Subject(s)
Blood-Brain Barrier/virology , Central Nervous System/virology , SARS-CoV-2/physiology , Virus Internalization , Antibodies/pharmacology , Benzamidines/pharmacology , COVID-19/pathology , COVID-19/virology , Endothelial Cells/cytology , Endothelial Cells/metabolism , Endothelial Cells/virology , Guanidines/pharmacology , Humans , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/metabolism , Models, Biological , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2/genetics , SARS-CoV-2/isolation & purification , Virus Internalization/drug effects
3.
Adv Sci (Weinh) ; 9(7): e2104192, 2022 03.
Article in English | MEDLINE | ID: covidwho-1589262

ABSTRACT

Coronavirus disease 2019 (COVID-19) patients with impact on skin and hair loss are reported. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is detected in the skin of some patients; however, the detailed pathological features of skin tissues from patients infected with SARS-CoV-2 at a molecular level are limited. Especially, the ability of SARS-CoV-2 to infect skin cells and impact their function is not well understood. A proteome map of COVID-19 skin is established here and the susceptibility of human-induced pluripotent stem cell (hiPSC)-derived skin organoids with hair follicles and nervous system is investigated, to SARS-CoV-2 infection. It is shown that KRT17+ hair follicles can be infected by SARS-CoV-2 and are associated with the impaired development of hair follicles and epidermis. Different types of nervous system cells are also found to be infected, which can lead to neuron death. Findings from the present work provide evidence for the association between COVID-19 and hair loss. hiPSC-derived skin organoids are also presented as an experimental model which can be used to investigate the susceptibility of skin cells to SARS-CoV-2 infection and can help identify various pathological mechanisms and drug screening strategies.


Subject(s)
COVID-19/physiopathology , Induced Pluripotent Stem Cells/cytology , Models, Biological , Organoids/cytology , Skin/cytology , COVID-19/virology , Hair Follicle/virology , Humans , Nervous System/virology , Proteomics , SARS-CoV-2/isolation & purification
4.
Cells ; 10(11)2021 11 11.
Article in English | MEDLINE | ID: covidwho-1533815

ABSTRACT

Cardiovascular disease (CVD) is one of the contributing factors to more than one-third of human mortality and the leading cause of death worldwide. The death of cardiac myocyte is a fundamental pathological process in cardiac pathologies caused by various heart diseases, including myocardial infarction. Thus, strategies for replacing fibrotic tissue in the infarcted region with functional myocardium have long been a goal of cardiovascular research. This review begins by briefly discussing a variety of somatic stem- and progenitor-cell populations that were frequently studied in early investigations of regenerative myocardial therapy and then focuses primarily on pluripotent stem cells (PSCs), especially induced-pluripotent stem cells (iPSCs), which have emerged as perhaps the most promising source of cardiomyocytes for both therapeutic applications and drug testing. We also describe attempts to generate cardiomyocytes directly from cardiac fibroblasts (i.e., transdifferentiation), which, if successful, may enable the pool of endogenous cardiac fibroblasts to be used as an in-situ source of cardiomyocytes for myocardial repair.


Subject(s)
Heart Failure/therapy , Myocardium/pathology , Regeneration/physiology , Stem Cell Transplantation , Animals , Clinical Trials as Topic , Humans , Induced Pluripotent Stem Cells/cytology
5.
Nat Commun ; 12(1): 652, 2021 01 28.
Article in English | MEDLINE | ID: covidwho-1397868

ABSTRACT

Injury and loss of oligodendrocytes can cause demyelinating diseases such as multiple sclerosis. To improve our understanding of human oligodendrocyte development, which could facilitate development of remyelination-based treatment strategies, here we describe time-course single-cell-transcriptomic analysis of developing human stem cell-derived oligodendrocyte-lineage-cells (hOLLCs). The study includes hOLLCs derived from both genome engineered embryonic stem cell (ESC) reporter cells containing an Identification-and-Purification tag driven by the endogenous PDGFRα promoter and from unmodified induced pluripotent (iPS) cells. Our analysis uncovers substantial transcriptional heterogeneity of PDGFRα-lineage hOLLCs. We discover sub-populations of human oligodendrocyte progenitor cells (hOPCs) including a potential cytokine-responsive hOPC subset, and identify candidate regulatory genes/networks that define the identity of these sub-populations. Pseudotime trajectory analysis defines developmental pathways of oligodendrocytes vs astrocytes from PDGFRα-expressing hOPCs and predicts differentially expressed genes between the two lineages. In addition, pathway enrichment analysis followed by pharmacological intervention of these pathways confirm that mTOR and cholesterol biosynthesis signaling pathways are involved in maturation of oligodendrocytes from hOPCs.


Subject(s)
Genetic Heterogeneity , Genetic Variation , Induced Pluripotent Stem Cells/metabolism , Oligodendrocyte Precursor Cells/metabolism , Single-Cell Analysis/methods , Transcriptome/genetics , Astrocytes/cytology , Astrocytes/metabolism , Cell Differentiation/genetics , Cell Line , Cell Lineage/genetics , Cholesterol/biosynthesis , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Gene Regulatory Networks/genetics , Humans , Induced Pluripotent Stem Cells/cytology , Oligodendrocyte Precursor Cells/cytology , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction/genetics , TOR Serine-Threonine Kinases/genetics , TOR Serine-Threonine Kinases/metabolism
6.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: covidwho-1389389

ABSTRACT

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.


Subject(s)
Central Nervous System Diseases/drug therapy , Drug Discovery/methods , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/drug effects , Tissue Engineering/methods , Animals , COVID-19/drug therapy , COVID-19/pathology , Central Nervous System Diseases/pathology , Drug Discovery/instrumentation , Drug Evaluation, Preclinical/instrumentation , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/pathology , Lab-On-A-Chip Devices , Organoids/cytology , Organoids/drug effects , Organoids/pathology , Tissue Engineering/instrumentation , Zika Virus Infection/drug therapy , Zika Virus Infection/pathology
7.
mSphere ; 6(3): e0027021, 2021 06 30.
Article in English | MEDLINE | ID: covidwho-1280401

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a wide variety of neurological complications. Even though SARS-CoV-2 is rarely detected in the central nervous system (CNS) or cerebrospinal fluid, evidence is accumulating that SARS-CoV-2 might enter the CNS via the olfactory nerve. However, what happens after SARS-CoV-2 enters the CNS is poorly understood. Therefore, we investigated the replication kinetics, cell tropism, and associated immune responses of SARS-CoV-2 infection in different types of neural cultures derived from human induced pluripotent stem cells (hiPSCs). SARS-CoV-2 was compared to the neurotropic and highly pathogenic H5N1 influenza A virus. SARS-CoV-2 infected a minority of individual mature neurons, without subsequent virus replication and spread, despite angiotensin-converting enzyme 2 (ACE2), transmembrane protease serine 2 (TMPRSS2), and neuropilin-1 (NPR1) expression in all cultures. However, this sparse infection did result in the production of type III interferons and interleukin-8 (IL-8). In contrast, H5N1 virus replicated and spread very efficiently in all cell types in all cultures. Taken together, our findings support the hypothesis that neurological complications might result from local immune responses triggered by virus invasion, rather than abundant SARS-CoV-2 replication in the CNS. IMPORTANCE Infections with the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are often associated with neurological complications. Evidence suggests that SARS-CoV-2 enters the brain via the olfactory nerve; however, SARS-CoV-2 is only rarely detected in the central nervous system of COVID-19 patients. Here, we show that SARS-CoV-2 is able to infect neurons of human iPSC neural cultures but that this infection is abortive and does not result in virus spread to other cells. However, infection of neural cultures did result in the production of type III interferon and IL-8. This study suggests that SARS-CoV-2 might enter the CNS and infect individual neurons, triggering local immune responses that could contribute to the pathogenesis of SARS-CoV-2-associated CNS disease.


Subject(s)
Induced Pluripotent Stem Cells/cytology , Influenza A Virus, H5N1 Subtype/physiology , Neurons/virology , SARS-CoV-2/physiology , Viral Tropism , Virus Replication , Animals , Brain Diseases/etiology , COVID-19/complications , Chlorocebus aethiops , Dogs , Humans , Influenza A Virus, H5N1 Subtype/immunology , Kinetics , Madin Darby Canine Kidney Cells , SARS-CoV-2/immunology , Vero Cells
8.
Stem Cell Reports ; 16(4): 940-953, 2021 04 13.
Article in English | MEDLINE | ID: covidwho-1180038

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to coronavirus disease 2019 (COVID-19) usually results in respiratory disease, but extrapulmonary manifestations are of major clinical interest. Intestinal symptoms of COVID-19 are present in a significant number of patients, and include nausea, diarrhea, and viral RNA shedding in feces. Human induced pluripotent stem cell-derived intestinal organoids (HIOs) represent an inexhaustible cellular resource that could serve as a valuable tool to study SARS-CoV-2 as well as other enteric viruses that infect the intestinal epithelium. Here, we report that SARS-CoV-2 productively infects both proximally and distally patterned HIOs, leading to the release of infectious viral particles while stimulating a robust transcriptomic response, including a significant upregulation of interferon-related genes that appeared to be conserved across multiple epithelial cell types. These findings illuminate a potential inflammatory epithelial-specific signature that may contribute to both the multisystemic nature of COVID-19 as well as its highly variable clinical presentation.


Subject(s)
COVID-19/pathology , Colon/pathology , Intestinal Mucosa/pathology , Organoids/pathology , Cell Line , Colon/virology , Epithelial Cells/virology , Humans , Induced Pluripotent Stem Cells/cytology , Inflammation/virology , Intestinal Mucosa/virology , Models, Biological , Organoids/cytology , Organoids/virology , SARS-CoV-2 , Virus Replication/physiology
9.
Int J Mol Sci ; 22(3)2021 Jan 28.
Article in English | MEDLINE | ID: covidwho-1055070

ABSTRACT

Angiotensin-converting enzyme 2 (ACE2) was identified as the main host cell receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its subsequent infection. In some coronavirus disease 2019 (COVID-19) patients, it has been reported that the nervous tissues and the eyes were also affected. However, evidence supporting that the retina is a target tissue for SARS-CoV-2 infection is still lacking. This present study aimed to investigate whether ACE2 expression plays a role in human retinal neurons during SARS-CoV-2 infection. Human induced pluripotent stem cell (hiPSC)-derived retinal organoids and monolayer cultures derived from dissociated retinal organoids were generated. To validate the potential entry of SARS-CoV-2 infection in the retina, we showed that hiPSC-derived retinal organoids and monolayer cultures endogenously express ACE2 and transmembrane serine protease 2 (TMPRSS2) on the mRNA level. Immunofluorescence staining confirmed the protein expression of ACE2 and TMPRSS2 in retinal organoids and monolayer cultures. Furthermore, using the SARS-CoV-2 pseudovirus spike protein with GFP expression system, we found that retinal organoids and monolayer cultures can potentially be infected by the SARS-CoV-2 pseudovirus. Collectively, our findings highlighted the potential of iPSC-derived retinal organoids as the models for ACE2 receptor-based SARS-CoV-2 infection.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Gene Expression , Induced Pluripotent Stem Cells/cytology , Retina/cytology , SARS-CoV-2/physiology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/metabolism , Cell Culture Techniques , Cell Line , Humans , Induced Pluripotent Stem Cells/metabolism , Organoids/cytology , Organoids/metabolism , Retina/metabolism , Serine Endopeptidases/genetics , Serine Endopeptidases/metabolism , Virus Internalization
10.
Int J Mol Sci ; 22(3)2021 Jan 26.
Article in English | MEDLINE | ID: covidwho-1050617

ABSTRACT

A high-throughput drug screen identifies potentially promising therapeutics for clinical trials. However, limitations that persist in current disease modeling with limited physiological relevancy of human patients skew drug responses, hamper translation of clinical efficacy, and contribute to high clinical attritions. The emergence of induced pluripotent stem cell (iPSC) technology revolutionizes the paradigm of drug discovery. In particular, iPSC-based three-dimensional (3D) tissue engineering that appears as a promising vehicle of in vitro disease modeling provides more sophisticated tissue architectures and micro-environmental cues than a traditional two-dimensional (2D) culture. Here we discuss 3D based organoids/spheroids that construct the advanced modeling with evolved structural complexity, which propels drug discovery by exhibiting more human specific and diverse pathologies that are not perceived in 2D or animal models. We will then focus on various central nerve system (CNS) disease modeling using human iPSCs, leading to uncovering disease pathogenesis that guides the development of therapeutic strategies. Finally, we will address new opportunities of iPSC-assisted drug discovery with multi-disciplinary approaches from bioengineering to Omics technology. Despite technological challenges, iPSC-derived cytoarchitectures through interactions of diverse cell types mimic patients' CNS and serve as a platform for therapeutic development and personalized precision medicine.


Subject(s)
Central Nervous System Diseases/drug therapy , Drug Discovery/methods , Induced Pluripotent Stem Cells/cytology , Induced Pluripotent Stem Cells/drug effects , Tissue Engineering/methods , Animals , COVID-19/drug therapy , COVID-19/pathology , Central Nervous System Diseases/pathology , Drug Discovery/instrumentation , Drug Evaluation, Preclinical/instrumentation , Drug Evaluation, Preclinical/methods , Humans , Induced Pluripotent Stem Cells/pathology , Lab-On-A-Chip Devices , Organoids/cytology , Organoids/drug effects , Organoids/pathology , Tissue Engineering/instrumentation , Zika Virus Infection/drug therapy , Zika Virus Infection/pathology
11.
Cell Rep ; 34(2): 108628, 2021 01 12.
Article in English | MEDLINE | ID: covidwho-1036973

ABSTRACT

Recent studies have profiled the innate immune signatures in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and suggest that cellular responses to viral challenge may affect disease severity. Yet the molecular events that underlie cellular recognition and response to SARS-CoV-2 infection remain to be elucidated. Here, we find that SARS-CoV-2 replication induces a delayed interferon (IFN) response in lung epithelial cells. By screening 16 putative sensors involved in sensing of RNA virus infection, we found that MDA5 and LGP2 primarily regulate IFN induction in response to SARS-CoV-2 infection. Further analyses revealed that viral intermediates specifically activate the IFN response through MDA5-mediated sensing. Additionally, we find that IRF3, IRF5, and NF-κB/p65 are the key transcription factors regulating the IFN response during SARS-CoV-2 infection. In summary, these findings provide critical insights into the molecular basis of the innate immune recognition and signaling response to SARS-CoV-2.


Subject(s)
Immunity, Innate , Interferon-Induced Helicase, IFIH1/metabolism , SARS-CoV-2/physiology , COVID-19/pathology , COVID-19/virology , Cell Line , Epithelial Cells/cytology , Epithelial Cells/immunology , Epithelial Cells/virology , Humans , Induced Pluripotent Stem Cells/cytology , Interferon Regulatory Factor-3/genetics , Interferon Regulatory Factor-3/metabolism , Interferon Regulatory Factors/genetics , Interferon Regulatory Factors/metabolism , Interferons/genetics , Interferons/metabolism , RNA Helicases/metabolism , RNA Interference , RNA, Double-Stranded/metabolism , RNA, Small Interfering/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Signal Transduction , Transcription Factor RelA/metabolism , Virus Replication
12.
Curr Protoc Stem Cell Biol ; 54(1): e118, 2020 09.
Article in English | MEDLINE | ID: covidwho-635380

ABSTRACT

The normal development of the pulmonary system is critical to transitioning from placental-dependent fetal life to alveolar-dependent newborn life. Human lung development and disease have been difficult to study due to the lack of an in vitro model system containing cells from the large airways and distal alveolus. This article describes a system that allows human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs) to differentiate and form three-dimensional (3D) structures that emulate the development, cytoarchitecture, and function of the lung ("organoids"), containing epithelial and mesenchymal cell populations, and including the production of surfactant and presence of ciliated cells. The organoids can also be invested with mesoderm derivatives, differentiated from the same human pluripotent stem cells, such as alveolar macrophages and vasculature. Such lung organoids may be used to study the impact of environmental modifiers and perturbagens (toxins, microbial or viral pathogens, alterations in microbiome) or the efficacy and safety of drugs, biologics, and gene transfer. © 2020 Wiley Periodicals LLC. Basic Protocol: hESC/hiPSC dissection, definitive endoderm formation, and lung progenitor cell induction.


Subject(s)
Coronavirus Infections/pathology , Lung/cytology , Organoids/cytology , Pneumonia, Viral/pathology , Respiratory Tract Infections/pathology , Betacoronavirus , COVID-19 , Cell Culture Techniques , Cell Differentiation , Coronavirus Infections/therapy , Endoderm/cytology , Human Embryonic Stem Cells/cytology , Humans , Induced Pluripotent Stem Cells/cytology , Lung/growth & development , Lung/physiology , Models, Biological , Pandemics , Patient-Specific Modeling , Pneumonia, Viral/therapy , Respiratory Tract Infections/therapy , SARS-CoV-2 , Time-Lapse Imaging
13.
Hum Genomics ; 14(1): 25, 2020 06 26.
Article in English | MEDLINE | ID: covidwho-617410

ABSTRACT

Human-induced pluripotent stem cells (hiPSCs) and CRISPR/Cas9 gene editing system represent two instruments of basic and translational research, which both allow to acquire deep insight about the molecular bases of many diseases but also to develop pharmacological research.This review is focused to draw up the latest technique of gene editing applied on hiPSCs, exploiting some of the genetic manipulation directed to the discovery of innovative therapeutic strategies. There are many expediencies provided by the use of hiPSCs, which can represent a disease model clinically relevant and predictive, with a great potential if associated to CRISPR/Cas9 technology, a gene editing tool powered by ease and precision never seen before.Here, we describe the possible applications of CRISPR/Cas9 to hiPSCs: from drug development to drug screening and from gene therapy to the induction of the immunological response to specific virus infection, such as HIV and SARS-Cov-2.


Subject(s)
CRISPR-Cas Systems , Drug Discovery , Gene Editing , Genetic Therapy , Induced Pluripotent Stem Cells/cytology , Virus Diseases/therapy , Animals , Cellular Reprogramming , Humans , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/transplantation , Virus Diseases/genetics
14.
J Mol Cell Cardiol ; 148: 46-49, 2020 11.
Article in English | MEDLINE | ID: covidwho-741564

ABSTRACT

The World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) as a public health emergency of international concern as more than 15 million cases were reported by 24th July 2020. Angiotensin-converting enzyme 2 (ACE2) is a COVID-19 entry receptor regulating host cell infection. A recent study reported that ACE2 is expressed in cardiomyocytes. In this study, we aimed to explore if there are microRNA (miRNA) molecules which target ACE2 and which may be exploited to regulate the SARS-CoV-2 receptor. Our data reveal that both Ace2 mRNA and Ace2 protein levels are inhibited by miR-200c in rat primary cardiomyocytes and importantly, in human iPSC-derived cardiomyocytes. We report the first miRNA candidate that can target ACE2 in cardiomyocytes and thus may be exploited as a preventive strategy to treat cardiovascular complications of COVID-19.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , MicroRNAs/genetics , Myocardium/metabolism , Myocytes, Cardiac/metabolism , Animals , COVID-19/virology , Cells, Cultured , Computer Simulation , Fibroblasts/metabolism , Human Umbilical Vein Endothelial Cells , Humans , Induced Pluripotent Stem Cells/cytology , Mice , Myocytes, Cardiac/virology , Rats , Real-Time Polymerase Chain Reaction , SARS-CoV-2
15.
Nature ; 586(7827): 113-119, 2020 10.
Article in English | MEDLINE | ID: covidwho-672174

ABSTRACT

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of the severe pneumonia-like disease coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to take at least 12-18 months, and the typical timeline for approval of a new antiviral therapeutic agent can exceed 10 years. Thus, repurposing of known drugs could substantially accelerate the deployment of new therapies for COVID-19. Here we profiled a library of drugs encompassing approximately 12,000 clinical-stage or Food and Drug Administration (FDA)-approved small molecules to identify candidate therapeutic drugs for COVID-19. We report the identification of 100 molecules that inhibit viral replication of SARS-CoV-2, including 21 drugs that exhibit dose-response relationships. Of these, thirteen were found to harbour effective concentrations commensurate with probable achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2-4 and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825 and ONO 5334. Notably, MDL-28170, ONO 5334 and apilimod were found to antagonize viral replication in human pneumocyte-like cells derived from induced pluripotent stem cells, and apilimod also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, their known pharmacological and human safety profiles will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.


Subject(s)
Antiviral Agents/analysis , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Evaluation, Preclinical , Drug Repositioning , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Alveolar Epithelial Cells/cytology , Alveolar Epithelial Cells/drug effects , Betacoronavirus/growth & development , COVID-19 , Cell Line , Cysteine Proteinase Inhibitors/analysis , Cysteine Proteinase Inhibitors/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Gene Expression Regulation/drug effects , Humans , Hydrazones , Induced Pluripotent Stem Cells/cytology , Models, Biological , Morpholines/analysis , Morpholines/pharmacology , Pandemics , Pyrimidines , Reproducibility of Results , SARS-CoV-2 , Small Molecule Libraries/analysis , Small Molecule Libraries/pharmacology , Triazines/analysis , Triazines/pharmacology , Virus Internalization/drug effects , Virus Replication/drug effects
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