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1.
Chest ; 161(1): e5-e11, 2022 01.
Article in English | MEDLINE | ID: covidwho-1595933

ABSTRACT

CASE PRESENTATION: A 67-year-old obese man (BMI 38.0) with type 2 diabetes mellitus (DM), chronic atrial fibrillation, and chronic lymphocytic leukemia stage II, stable for 8 years after chemotherapy, and a history of smoking presented to the ED with progressive dyspnea and fever due to SARS-CoV-2 infection. He was admitted to a general ward and treated with dexamethasone (6 mg IV once daily) and oxygen. On day 3 of hospital admission, he became progressively hypoxemic and was admitted to the ICU for invasive mechanical ventilation. Dexamethasone treatment was continued, and a single dose of tocilizumab (800 mg) was administered. On day 9 of ICU admission, voriconazole treatment was initiated after tracheal white plaques at bronchoscopy, suggestive of invasive Aspergillus tracheobronchitis, were noticed. However, his medical situation dramatically deteriorated.


Subject(s)
Acute Kidney Injury/virology , Antifungal Agents/therapeutic use , COVID-19/complications , Mucormycosis/diagnosis , Mucormycosis/drug therapy , Pulmonary Aspergillosis/diagnosis , Pulmonary Aspergillosis/drug therapy , Aged , Amphotericin B/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Atrial Fibrillation/complications , Bronchoscopy , Dexamethasone/therapeutic use , Diabetes Mellitus, Type 2/complications , Fatal Outcome , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complications , Male , Nitriles/therapeutic use , Obesity/complications , Oxygen Inhalation Therapy , Pyridines/therapeutic use , Respiration, Artificial , SARS-CoV-2 , Smoking/adverse effects , Tomography, X-Ray Computed , Triazoles/therapeutic use , Voriconazole/therapeutic use
2.
Mol Cancer Res ; 20(3): 446-455, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1518187

ABSTRACT

AXL, a receptor tyrosine kinase from the TAM (TYRO3 AXL and MER) subfamily, and its ligand growth arrest-specific 6 (GAS6) are implicated in pathogenesis of a wide array of cancers, acquisition of resistance to diverse anticancer therapies and cellular entry of viruses. The continuous development of AXL inhibitors for treatment of patients with cancer and COVID-19 underscores the need to better characterize the cellular effects of AXL targeting.In the present study, we compared the cellular phenotypes of CRISPR-Cas9-induced depletion of AXL and its pharmacological inhibition with bemcentinib, LDC1267 and gilteritinib. Specifically, we evaluated GAS6-AXL signaling, cell viability and invasion, the endo-lysosomal system and autophagy in glioblastoma cells. We showed that depletion of AXL but not of TYRO3 inhibited GAS6-induced phosphorylation of downstream signaling effectors, AKT and ERK1/2, indicating that AXL is a primary receptor for GAS6. AXL was also specifically required for GAS6-dependent increase in cell viability but was dispensable for viability of cells grown without exogenous addition of GAS6. Furthermore, we revealed that LDC1267 is the most potent and specific inhibitor of AXL activation among the tested compounds. Finally, we found that, in contrast to AXL depletion and its inhibition with LDC1267, cell treatment with bemcentinib and gilteritinib impaired the endo-lysosomal and autophagy systems in an AXL-independent manner. IMPLICATIONS: Altogether, our findings are of high clinical importance as we discovered that two clinically advanced AXL inhibitors, bemcentinib and gilteritinib, may display AXL-independent cellular effects and toxicity.


Subject(s)
Aniline Compounds/therapeutic use , Benzocycloheptenes/therapeutic use , Lysosomes/drug effects , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins/antagonists & inhibitors , Pyrazines/therapeutic use , Receptor Protein-Tyrosine Kinases/antagonists & inhibitors , Triazoles/therapeutic use , Aniline Compounds/pharmacology , Autophagy , Benzocycloheptenes/pharmacology , Cell Line, Tumor , Cell Proliferation , Humans , Protein Kinase Inhibitors/pharmacology , Pyrazines/pharmacology , Signal Transduction , Transfection , Triazoles/pharmacology
3.
Molecules ; 26(20)2021 Oct 14.
Article in English | MEDLINE | ID: covidwho-1470936

ABSTRACT

The SARS-CoV-2 virus is highly contagious to humans and has caused a pandemic of global proportions. Despite worldwide research efforts, efficient targeted therapies against the virus are still lacking. With the ready availability of the macromolecular structures of coronavirus and its known variants, the search for anti-SARS-CoV-2 therapeutics through in silico analysis has become a highly promising field of research. In this study, we investigate the inhibiting potentialities of triazole-based compounds against the SARS-CoV-2 main protease (Mpro). The SARS-CoV-2 main protease (Mpro) is known to play a prominent role in the processing of polyproteins that are translated from the viral RNA. Compounds were pre-screened from 171 candidates (collected from the DrugBank database). The results showed that four candidates (Bemcentinib, Bisoctrizole, PYIITM, and NIPFC) had high binding affinity values and had the potential to interrupt the main protease (Mpro) activities of the SARS-CoV-2 virus. The pharmacokinetic parameters of these candidates were assessed and through molecular dynamic (MD) simulation their stability, interaction, and conformation were analyzed. In summary, this study identified the most suitable compounds for targeting Mpro, and we recommend using these compounds as potential drug molecules against SARS-CoV-2 after follow up studies.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Triazoles/chemistry , Antiviral Agents/metabolism , Antiviral Agents/therapeutic use , Benzocycloheptenes/chemistry , Benzocycloheptenes/metabolism , Binding Sites , COVID-19/drug therapy , COVID-19/virology , Coronavirus 3C Proteases/metabolism , Databases, Chemical , Half-Life , Humans , Ligands , Molecular Docking Simulation , Molecular Dynamics Simulation , Protease Inhibitors/metabolism , Protease Inhibitors/therapeutic use , Protein Binding , Quantitative Structure-Activity Relationship , SARS-CoV-2/isolation & purification , Triazoles/metabolism , Triazoles/therapeutic use
4.
Crit Care ; 25(1): 335, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1412565

ABSTRACT

BACKGROUND: Coronavirus disease 19 (COVID-19)-associated pulmonary aspergillosis (CAPA) emerged as important fungal complications in patients with COVID-19-associated severe acute respiratory failure (ARF). Whether mould active antifungal prophylaxis (MAFP) can prevent CAPA remains elusive so far. METHODS: In this observational study, we included all consecutive patients admitted to intensive care units with COVID-19-associated ARF between September 1, 2020, and May 1, 2021. We compared patients with versus without antifungal prophylaxis with respect to CAPA incidence (primary outcome) and mortality (secondary outcome). Propensity score adjustment was performed to account for any imbalances in baseline characteristics. CAPA cases were classified according to European Confederation of Medical Mycology (ECMM)/International Society of Human and Animal Mycoses (ISHAM) consensus criteria. RESULTS: We included 132 patients, of whom 75 (57%) received antifungal prophylaxis (98% posaconazole). Ten CAPA cases were diagnosed, after a median of 6 days following ICU admission. Of those, 9 CAPA cases were recorded in the non-prophylaxis group and one in the prophylaxis group, respectively. However, no difference in 30-day ICU mortality could be observed. Thirty-day CAPA incidence estimates were 1.4% (95% CI 0.2-9.7) in the MAFP group and 17.5% (95% CI 9.6-31.4) in the group without MAFP (p = 0.002). The respective subdistributional hazard ratio (sHR) for CAPA incidence comparing the MAFP versus no MAFP group was of 0.08 (95% CI 0.01-0.63; p = 0.017). CONCLUSION: In ICU patients with COVID-19 ARF, antifungal prophylaxis was associated with significantly reduced CAPA incidence, but this did not translate into improved survival. Randomized controlled trials are warranted to evaluate the efficacy and safety of MAFP with respect to CAPA incidence and clinical outcomes.


Subject(s)
Antifungal Agents/therapeutic use , COVID-19/complications , Pulmonary Aspergillosis/prevention & control , Aged , COVID-19/mortality , Critical Illness , Female , Humans , Intensive Care Units , Male , Middle Aged , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/mortality , Triazoles/therapeutic use
5.
Mycoses ; 64(10): 1238-1252, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1314088

ABSTRACT

PURPOSE: The aim of the study was to report clinical features, contributing factors and outcome of patients with coronavirus disease 2019 (COVID-19)-associated mucormycosis (CAM). METHODS: A cross-sectional descriptive multicentre study was conducted on patients with biopsy-proven mucormycosis with RT-PCR-confirmed COVID-19 from April to September 2020. Demographics, the time interval between COVID-19 and mucormycosis, underlying systemic diseases, clinical features, course of disease and outcomes were collected and analysed. RESULTS: Fifteen patients with COVID-19 and rhino-orbital mucormycosis were observed. The median age of patients was 52 years (range 14-71), and 66% were male. The median interval time between COVID-19 disease and diagnosis of mucormycosis was seven (range: 1-37) days. Among all, 13 patients (86%) had diabetes mellitus, while 7 (46.6%) previously received intravenous corticosteroid therapy. Five patients (33%) underwent orbital exenteration, while seven (47%) patients died from mucormycosis. Six patients (40%) received combined antifungal therapy and none that received combined antifungal therapy died. CONCLUSION: Clinicians should be aware that mucormycosis may be complication of COVID-19 in high-risk patients. Poor control of diabetes mellitus is an important predisposing factor for CAM. Systematic surveillance for control of diabetes mellitus and educating physician about the early diagnosis of CAM are suggested.


Subject(s)
Antifungal Agents/therapeutic use , COVID-19/complications , Coinfection , Mucormycosis/drug therapy , Mucormycosis/mortality , Respiratory Distress Syndrome/mortality , Adolescent , Adult , Aged , Amphotericin B/therapeutic use , COVID-19/drug therapy , COVID-19/pathology , Caspofungin/therapeutic use , Comorbidity , Cross-Sectional Studies , Diabetes Complications/microbiology , Diabetes Complications/mortality , Diabetes Mellitus/pathology , Drug Therapy, Combination , Female , Humans , Iran , Male , Middle Aged , Mucormycosis/pathology , Respiratory Distress Syndrome/microbiology , Respiratory Distress Syndrome/pathology , Triazoles/therapeutic use , Young Adult
6.
Mycoses ; 64(8): 798-808, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1085281

ABSTRACT

Acute respiratory distress syndrome is a common complication of severe viral pneumonia, such as influenza and COVID-19, that requires critical care including ventilatory support, use of corticosteroids and other adjunctive therapies to arrest the attendant massive airways inflammation. Although recommended for the treatment of viral pneumonia, steroid therapy appears to be a double-edged sword, predisposing patients to secondary bacterial and invasive fungal infections (IFIs) whereby impacting morbidity and mortality. Mucormycosis is a fungal emergency with a highly aggressive tendency for contiguous spread, associated with a poor prognosis if not promptly diagnosed and managed. Classically, uncontrolled diabetes mellitus (DM) and other immunosuppressive conditions including corticosteroid therapy are known risk factors for mucormycosis. Upon the background lung pathology, immune dysfunction and corticosteroid therapy, patients with severe viral pneumonia are likely to develop IFIs like aspergillosis and mucormycosis. Notably, the combination of steroid therapy and DM can augment immunosuppression and hyperglycaemia, increasing the risk of mucormycosis in a susceptible individual. Here, we report a case of sinonasal mucormycosis in a 44-year-old woman with hyperglycaemia secondary to poorly controlled diabetes following dexamethasone therapy on a background of influenza pneumonia and review 15 available literatures on reported cases of influenza and COVID-19 associated mucormycosis.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/complications , Influenza, Human/complications , Mucormycosis/drug therapy , Mucormycosis/etiology , Pneumonia, Viral/drug therapy , Adult , Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Diabetes Complications , Female , Humans , Liposomes/therapeutic use , Triazoles/therapeutic use
7.
J Med Chem ; 64(1): 890-904, 2021 01 14.
Article in English | MEDLINE | ID: covidwho-997768

ABSTRACT

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.


Subject(s)
Pain Management/methods , Receptors, sigma/antagonists & inhibitors , Triazoles/chemistry , Animals , Binding Sites , Blood-Brain Barrier/metabolism , Drug Design , Guinea Pigs , Half-Life , Humans , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Neuralgia/chemically induced , Neuralgia/drug therapy , Protein Structure, Tertiary , Quantitative Structure-Activity Relationship , Rats , Receptors, sigma/metabolism , Triazoles/metabolism , Triazoles/therapeutic use
8.
Transpl Infect Dis ; 23(2): e13501, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-949310

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might increase the risk of invasive pulmonary aspergillosis (IPA). Although several case reports and small series have been reported in the general population, scarce information is available regarding coronavirus disease 2019 (COVID-19)-associated IPA in the setting of solid organ transplantation. We describe a case of a kidney transplant recipient with severe COVID-19 that was subsequently diagnosed with probable IPA on the basis of the repeated isolation of Aspergillus fumigatus in sputum cultures, repeatedly increased serum (1 â†’ 3)-ß-d-glucan levels, and enlarging cavitary nodules in the CT scan. The evolution was favorable after initiation of isavuconazole and nebulized liposomal amphotericin B combination therapy and the withdrawal of immunosuppression.


Subject(s)
Antifungal Agents/therapeutic use , COVID-19/therapy , Immunosuppressive Agents/adverse effects , Invasive Pulmonary Aspergillosis/drug therapy , Kidney Failure, Chronic/therapy , Kidney Transplantation , Acute Kidney Injury , Administration, Inhalation , Amphotericin B/administration & dosage , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Azithromycin/therapeutic use , COVID-19/complications , COVID-19/immunology , Ceftriaxone/therapeutic use , Deprescriptions , Female , Glucocorticoids/adverse effects , Graft Rejection/prevention & control , Humans , Hydroxychloroquine/therapeutic use , Hyperoxaluria, Primary/complications , Hyperoxaluria, Primary/diagnosis , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Invasive Pulmonary Aspergillosis/complications , Invasive Pulmonary Aspergillosis/diagnostic imaging , Invasive Pulmonary Aspergillosis/immunology , Kidney Failure, Chronic/etiology , Kidney Failure, Chronic/pathology , Middle Aged , Mycophenolic Acid/adverse effects , Nitriles/therapeutic use , Oxygen Inhalation Therapy , Prednisone/adverse effects , Pyridines/therapeutic use , Renal Dialysis , SARS-CoV-2 , Sputum , Tacrolimus/adverse effects , Tomography, X-Ray Computed , Triazoles/therapeutic use
9.
Sci Adv ; 6(47)2020 11.
Article in English | MEDLINE | ID: covidwho-887414

ABSTRACT

To affect the COVID-19 pandemic, lifesaving antiviral therapies must be identified. The number of clinical trials that can be performed is limited. We developed mathematical models to project multiple therapeutic approaches. Our models recapitulate off-treatment viral dynamics and predict a three-phase immune response. Simulated treatment with remdesivir, selinexor, neutralizing antibodies, or cellular immunotherapy demonstrates that rapid viral elimination is possible if in vivo potency is sufficiently high. Therapies dosed soon after peak viral load when symptoms develop may decrease shedding duration and immune response intensity but have little effect on viral area under the curve (AUC), which is driven by high early viral loads. Potent therapy dosed before viral peak during presymptomatic infection could lower AUC. Drug resistance may emerge with a moderately potent agent dosed before viral peak. Our results support early treatment for COVID-19 if shedding duration, not AUC, is most predictive of clinical severity.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adoptive Transfer/methods , Alanine/analogs & derivatives , Antibodies, Viral/therapeutic use , Antiviral Agents/therapeutic use , Broadly Neutralizing Antibodies/therapeutic use , COVID-19/drug therapy , Cell- and Tissue-Based Therapy/methods , Hydrazines/therapeutic use , SARS-CoV-2/physiology , Triazoles/therapeutic use , Virus Shedding/drug effects , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/therapeutic use , Alanine/pharmacokinetics , Alanine/therapeutic use , Antiviral Agents/pharmacokinetics , COVID-19/immunology , COVID-19/virology , Humans , Killer Cells, Natural/immunology , Models, Theoretical , Time Factors , Treatment Outcome , Viral Load/drug effects
10.
Curr Opin Infect Dis ; 33(4): 290-297, 2020 08.
Article in English | MEDLINE | ID: covidwho-641651

ABSTRACT

PURPOSE OF REVIEW: Although clinical outcomes in the treatment of aspergillosis have markedly improved with the availability of newer triazoles, the development of resistance to these antifungals, especially in Aspergillus fumigatus, is a growing concern. The purpose of this review is to provide an update on azole resistance mechanisms and their epidemiology in A. fumigatus, the clinical implications of azole resistance, and to discuss future treatment options against azole-resistant aspergillosis. RECENT FINDINGS: Resistance may develop through either patient or environmental azole exposure. Environmental exposure is the most prevalent means of resistance development, and these isolates can cause disease in various at-risk groups, which now include those with influenza, and potentially COVID-19. Although current treatment options are limited, newer therapies are in clinical development. These include agents with novel mechanisms of action which have in vitro and in vivo activity against azole-resistant A. fumigatus. SUMMARY: Azole-resistant A. fumigatus is an emerging threat that hampers our ability to successfully treat patients with aspergillosis. Certain geographic regions and patient populations appear to be at increased risk for this pathogen. As new patient groups are increasingly recognized to be at increased risk for invasive aspergillosis, studies to define the epidemiology and management of azole-resistant A. fumigatus are critically needed. While treatment options are currently limited, new agents under clinical development may offer hope.


Subject(s)
Antifungal Agents/pharmacology , Aspergillosis/immunology , Aspergillus fumigatus/immunology , Coronavirus Infections/immunology , Drug Resistance, Multiple, Fungal/immunology , Pneumonia, Viral/immunology , Triazoles/pharmacology , Antifungal Agents/therapeutic use , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillus fumigatus/drug effects , Betacoronavirus/immunology , COVID-19 , Environmental Exposure , Humans , Immunocompromised Host/immunology , Microbial Sensitivity Tests , Pandemics , SARS-CoV-2 , Triazoles/therapeutic use
11.
Psychosomatics ; 61(5): 544-550, 2020.
Article in English | MEDLINE | ID: covidwho-616923
12.
Mycoses ; 63(6): 528-534, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-547397

ABSTRACT

OBJECTIVES: Patients with acute respiratory distress syndrome (ARDS) due to viral infection are at risk for secondary complications like invasive aspergillosis. Our study evaluates coronavirus disease 19 (COVID-19) associated invasive aspergillosis at a single centre in Cologne, Germany. METHODS: A retrospective chart review of all patients with COVID-19 associated ARDS admitted to the medical or surgical intensive care unit at the University Hospital of Cologne, Cologne, Germany. RESULTS: COVID-19 associated invasive pulmonary aspergillosis was found in five of 19 consecutive critically ill patients with moderate to severe ARDS. CONCLUSION: Clinicians caring for patients with ARDS due to COVID-19 should consider invasive pulmonary aspergillosis and subject respiratory samples to comprehensive analysis to detect co-infection.


Subject(s)
Coronavirus Infections/complications , Pneumonia, Viral/complications , Pulmonary Aspergillosis/complications , Respiratory Distress Syndrome/complications , Aged , Antifungal Agents/therapeutic use , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/virology , COVID-19 , Coronavirus Infections/diagnostic imaging , Female , Galactose/analogs & derivatives , Germany , Hemorrhage/etiology , Hospitals, Teaching , Humans , Intensive Care Units , Lung Diseases/etiology , Male , Mannans/analysis , Metapneumovirus/isolation & purification , Middle Aged , Nitriles/therapeutic use , Pandemics , Paramyxoviridae Infections/etiology , Pneumonia, Viral/diagnostic imaging , Pulmonary Aspergillosis/diagnostic imaging , Pyridines/therapeutic use , Respiratory Distress Syndrome/diagnostic imaging , Retrospective Studies , Thorax/diagnostic imaging , Tomography, X-Ray Computed , Triazoles/therapeutic use , Voriconazole/therapeutic use
13.
Curr Mol Med ; 21(8): 645-654, 2021.
Article in English | MEDLINE | ID: covidwho-326955

ABSTRACT

BACKGROUND: Triazavirin (2-methylsulfanyl-6-nitro[1,2,4]triazolo[5,1-c][1,2,4] triazin-7(4H)-one, TZV) is an antiviral drug synthesized. TZV is being investigated for potential application against the Coronavirus 2019-nCoV. AIMS AND OBJECTIVES: In order to find candidate drugs for 2019-nCoV, we have carried out a computational study to screen for effective available drug Triazavirin (C5H4N6O3S) which may work as inhibitor for the Mpro of 2019-nCoV. METHODS: In the present work, first time the molecular structure of title molecule has been investigated using Density Functional Theory (DFT/B3LYP/MidiX) in gas phase. RESULTS: The molecular HOMO-LUMO, excitation energies and oscillator strengths of investigated compound have also been calculated and presented. The interaction of TZV compound with the Coronavirus was performed by molecular docking studies. CONCLUSION: Therefore, TZV can be used for potential application against the Coronavirus 2019-nCoV.


Subject(s)
COVID-19/drug therapy , SARS-CoV-2/drug effects , Triazines/therapeutic use , Triazoles/therapeutic use , COVID-19/virology , Density Functional Theory , Humans , Molecular Docking Simulation , Molecular Structure , Triazines/chemistry , Triazoles/chemistry
14.
FASEB J ; 34(6): 7253-7264, 2020 06.
Article in English | MEDLINE | ID: covidwho-175986

ABSTRACT

Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID-19. By describing the life cycle of the newly emergent coronavirus, SARS-CoV-2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID-19. Moreover, we propose that Niemann-Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS-CoV-2, by highlighting key established features of the disorder that together result in an "unfavorable" host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID-19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC-like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID-19.


Subject(s)
Antiviral Agents/pharmacokinetics , Betacoronavirus/physiology , Coronavirus Infections/drug therapy , Drug Repositioning , Endosomes/virology , Hydroxychloroquine/pharmacology , Lysosomes/virology , Niemann-Pick Disease, Type C/pathology , Pneumonia, Viral/drug therapy , ADAM17 Protein/physiology , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Angiotensin-Converting Enzyme 2 , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Benzylisoquinolines/pharmacology , Benzylisoquinolines/therapeutic use , Biological Transport , COVID-19 , Cathepsin L/physiology , Endocytosis , Endosomes/drug effects , Endosomes/physiology , Glycopeptides/pharmacology , Glycopeptides/therapeutic use , Humans , Hydroxychloroquine/pharmacokinetics , Hydroxychloroquine/therapeutic use , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Intracellular Signaling Peptides and Proteins/deficiency , Intracellular Signaling Peptides and Proteins/physiology , Lysosomes/drug effects , Lysosomes/metabolism , Membrane Lipids/metabolism , Membrane Microdomains/physiology , Niemann-Pick C1 Protein , Niemann-Pick Disease, Type C/metabolism , Oxysterols/metabolism , Pandemics , Peptidyl-Dipeptidase A/metabolism , Receptors, Virus/metabolism , SARS-CoV-2 , Serine Endopeptidases/physiology , Triazoles/pharmacology , Triazoles/therapeutic use , Virus Internalization/drug effects
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