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1.
ACS Chem Biol ; 17(5): 1239-1248, 2022 05 20.
Article in English | MEDLINE | ID: covidwho-1805550

ABSTRACT

Methicillin-resistant Staphylococcus aureus (MRSA) is a major threat to human health, as the US mortality rate outweighs those from HIV, tuberculosis, and viral hepatitis combined. In the wake of the COVID-19 pandemic, antibiotic-resistant bacterial infections acquired during hospital stays have increased. Antibiotic adjuvants are a key strategy to combat these bacteria. We have evaluated several small molecule antibiotic adjuvants that have strong potentiation with ß-lactam antibiotics and are likely inhibiting a master regulatory kinase, Stk1. Here, we investigated how the lead adjuvant (compound 8) exerts its effects in a more comprehensive manner. We hypothesized that the expression levels of key resistance genes would decrease once cotreated with oxacillin and the adjuvant. Furthermore, bioinformatic analyses would reveal biochemical pathways enriched in differentially expressed genes. RNA-seq analysis showed 176 and 233 genes significantly up- and downregulated, respectively, in response to cotreatment. Gene ontology categories and biochemical pathways that were significantly enriched with downregulated genes involved carbohydrate utilization, such as the citrate cycle and the phosphotransferase system. One of the most populated pathways was S. aureus infection. Results from an interaction network constructed with affected gene products supported the hypothesis that Stk1 is a target of compound 8. This study revealed a dramatic impact of our lead adjuvant on the transcriptome that is consistent with a pleiotropic effect due to Stk1 inhibition. These results point to this antibiotic adjuvant having potential broad therapeutic use in combatting MRSA.


Subject(s)
COVID-19 , Methicillin-Resistant Staphylococcus aureus , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Carbazoles/pharmacology , Humans , Methicillin-Resistant Staphylococcus aureus/genetics , Microbial Sensitivity Tests , Pandemics , Staphylococcus aureus , Transcriptome
2.
Viruses ; 13(12)2021 12 16.
Article in English | MEDLINE | ID: covidwho-1576965

ABSTRACT

Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus, causes neonatal pig acute gastrointestinal infection with a characterization of severe diarrhea, vomiting, high morbidity, and high mortality, resulting in tremendous damages to the swine industry. Neither specific antiviral drugs nor effective vaccines are available, posing a high priority to screen antiviral drugs. The aim of this study is to investigate anti-PEDV effects of carbazole alkaloid derivatives. Eighteen carbazole derivatives (No.1 to No.18) were synthesized, and No.5, No.7, and No.18 were identified to markedly reduce the replication of enhanced green fluorescent protein (EGFP) inserted-PEDV, and the mRNA level of PEDV N. Flow cytometry assay, coupled with CCK8 assay, confirmed No.7 and No.18 carbazole derivatives displayed high inhibition effects with low cell toxicity. Furthermore, time course analysis indicated No.7 and No.18 carbazole derivatives exerted inhibition at the early stage of the viral life cycle. Collectively, the analysis underlines the benefit of carbazole derivatives as potential inhibitors of PEDV, and provides candidates for the development of novel therapeutic agents.


Subject(s)
Antiviral Agents/pharmacology , Carbazoles/pharmacology , Porcine epidemic diarrhea virus/drug effects , Animals , Antiviral Agents/chemistry , Carbazoles/chemistry , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Molecular Structure , Vero Cells , Virus Attachment/drug effects , Virus Replication/drug effects
3.
Antiviral Res ; 194: 105167, 2021 10.
Article in English | MEDLINE | ID: covidwho-1370440

ABSTRACT

Niemann-Pick type C1 (NPC1) receptor is an endosomal membrane protein that regulates intracellular cholesterol traffic. This protein has been shown to play an important role for several viruses. It has been reported that SARS-CoV-2 enters the cell through plasma membrane fusion and/or endosomal entry upon availability of proteases. However, the whole process is not fully understood yet and additional viral/host factors might be required for viral fusion and subsequent viral replication. Here, we report a novel interaction between the SARS-CoV-2 nucleoprotein (N) and the cholesterol transporter NPC1. Furthermore, we have found that some compounds reported to interact with NPC1, carbazole SC816 and sulfides SC198 and SC073, were able to reduce SARS-CoV-2 viral infection with a good selectivity index in human cell infection models. These findings suggest the importance of NPC1 for SARS-CoV-2 viral infection and a new possible potential therapeutic target to fight against COVID-19.


Subject(s)
Biological Transport , COVID-19/drug therapy , Endosomes/virology , Niemann-Pick C1 Protein/analysis , SARS-CoV-2/physiology , Animals , Carbazoles/pharmacology , Chlorocebus aethiops , Endosomes/chemistry , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins , Membrane Fusion , Vero Cells , Virus Replication
4.
Sci Rep ; 11(1): 16629, 2021 08 17.
Article in English | MEDLINE | ID: covidwho-1361646

ABSTRACT

Since understanding molecular mechanisms of SARS-CoV-2 infection is extremely important for developing effective therapies against COVID-19, we focused on the internalization mechanism of SARS-CoV-2 via ACE2. Although cigarette smoke is generally believed to be harmful to the pathogenesis of COVID-19, cigarette smoke extract (CSE) treatments were surprisingly found to suppress the expression of ACE2 in HepG2 cells. We thus tried to clarify the mechanism of CSE effects on expression of ACE2 in mammalian cells. Because RNA-seq analysis suggested that suppressive effects on ACE2 might be inversely correlated with induction of the genes regulated by aryl hydrocarbon receptor (AHR), the AHR agonists 6-formylindolo(3,2-b)carbazole (FICZ) and omeprazole (OMP) were tested to assess whether those treatments affected ACE2 expression. Both FICZ and OMP clearly suppressed ACE2 expression in a dose-dependent manner along with inducing CYP1A1. Knock-down experiments indicated a reduction of ACE2 by FICZ treatment in an AHR-dependent manner. Finally, treatments of AHR agonists inhibited SARS-CoV-2 infection into Vero E6 cells as determined with immunoblotting analyses detecting SARS-CoV-2 specific nucleocapsid protein. We here demonstrate that treatment with AHR agonists, including FICZ, and OMP, decreases expression of ACE2 via AHR activation, resulting in suppression of SARS-CoV-2 infection in mammalian cells.


Subject(s)
Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Basic Helix-Loop-Helix Transcription Factors/agonists , COVID-19/drug therapy , Carbazoles/pharmacology , Omeprazole/pharmacology , Receptors, Aryl Hydrocarbon/agonists , Angiotensin-Converting Enzyme 2/genetics , Angiotensin-Converting Enzyme 2/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , COVID-19/virology , Carbazoles/therapeutic use , Chlorocebus aethiops , Cytochrome P-450 CYP1A1/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Gene Expression Regulation/drug effects , Gene Knockdown Techniques , Hep G2 Cells , Humans , Omeprazole/therapeutic use , RNA-Seq , Receptors, Aryl Hydrocarbon/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Signal Transduction/drug effects , Vero Cells , Virus Internalization/drug effects
5.
Int Immunopharmacol ; 99: 108012, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1330894

ABSTRACT

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Carbazoles/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib/pharmacology , Lung Neoplasms/drug therapy , Piperidines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/secondary , Drug Interactions , Humans , Kidney Transplantation , Lung Neoplasms/pathology , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology
6.
Virus Res ; 292: 198246, 2021 01 15.
Article in English | MEDLINE | ID: covidwho-974719

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic has created an urgent need for therapeutics that inhibit the SARS-COV-2 virus and suppress the fulminant inflammation characteristic of advanced illness. Here, we describe the anti-COVID-19 potential of PTC299, an orally bioavailable compound that is a potent inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme of the de novo pyrimidine nucleotide biosynthesis pathway. In tissue culture, PTC299 manifests robust, dose-dependent, and DHODH-dependent inhibition of SARS-COV-2 replication (EC50 range, 2.0-31.6 nM) with a selectivity index >3,800. PTC299 also blocked replication of other RNA viruses, including Ebola virus. Consistent with known DHODH requirements for immunomodulatory cytokine production, PTC299 inhibited the production of interleukin (IL)-6, IL-17A (also called IL-17), IL-17 F, and vascular endothelial growth factor (VEGF) in tissue culture models. The combination of anti-SARS-CoV-2 activity, cytokine inhibitory activity, and previously established favorable pharmacokinetic and human safety profiles render PTC299 a promising therapeutic for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Carbamates/pharmacology , Carbazoles/pharmacology , Cytokines/antagonists & inhibitors , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , SARS-CoV-2/drug effects , Virus Replication/drug effects , Animals , COVID-19/drug therapy , Chlorocebus aethiops , Cytokine Release Syndrome/drug therapy , Cytokines/immunology , HeLa Cells , Humans , Inflammation/drug therapy , Inflammation/virology , Vero Cells
7.
Eur J Cancer ; 138: 109-112, 2020 10.
Article in English | MEDLINE | ID: covidwho-739806
8.
Med Hypotheses ; 143: 110122, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-663829

ABSTRACT

A characteristic feature of COVID-19 disease is lymphopenia. Lymphopenia occurs early in the clinical course and is a predictor of disease severity and outcomes. The mechanism of lymphopenia in COVID-19 is uncertain. It has been variously attributed to the release of inflammatory cytokines including IL-6 and TNF-α; direct infection of the lymphocytes by the virus; and rapid sequestration of lymphocytes in the tissues. Additionally, we postulate that prostaglandin D2 (PGD2) is a key meditator of lymphopenia in COVID-19. First, SARS-CoV infection is known to stimulate the production of PGD2 in the airways, which inhibits the host dendritic cell response via the DP1 receptor signaling. Second, PGD2 is known to upregulate monocytic myeloid-derived suppressor cells (MDSC) via the DP2 receptor signaling in group 2 innate lymphoid cells (ILC2). We propose targeting PGD2/DP2 signaling using a receptor antagonist such as ramatroban as an immunotherapy for immune dysfunction and lymphopenia in COVID-19 disease.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Lymphopenia/physiopathology , Models, Immunological , Molecular Targeted Therapy , Pandemics , Pneumonia, Viral/physiopathology , Prostaglandin D2/physiology , Respiratory System/metabolism , Adult , COVID-19 , Carbazoles/pharmacology , Carbazoles/therapeutic use , Child , Coronavirus Infections/complications , Coronavirus Infections/immunology , Dendritic Cells/immunology , Humans , Lymphopenia/etiology , Myeloid Cells/immunology , Pneumonia, Viral/complications , Pneumonia, Viral/immunology , Prostaglandin D2/biosynthesis , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Receptors, Prostaglandin/metabolism , Receptors, Prostaglandin/physiology , SARS-CoV-2 , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , T-Lymphocytes/immunology , Thromboxane A2/antagonists & inhibitors
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