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1.
Int J Mol Sci ; 22(22)2021 Nov 16.
Article in English | MEDLINE | ID: covidwho-1534087

ABSTRACT

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.


Subject(s)
Antineoplastic Agents/pharmacology , Apolipoproteins E/genetics , Bexarotene/pharmacology , Leukocytes/drug effects , Nicotinic Acids/pharmacology , Retinoid X Receptor alpha/agonists , Animals , Antineoplastic Agents/chemical synthesis , Apolipoproteins E/metabolism , Bexarotene/analogs & derivatives , Bexarotene/chemical synthesis , Cell Line, Tumor , Dose-Response Relationship, Drug , Gene Expression , Humans , Leukocytes/metabolism , Leukocytes/pathology , Nicotinic Acids/chemical synthesis , Retinoid X Receptor alpha/genetics , Retinoid X Receptor alpha/metabolism , Structure-Activity Relationship
2.
Int Immunopharmacol ; 101(Pt A): 108292, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1487772

ABSTRACT

Leukopenia is a common manifestation of many diseases, including global outbreak SAS-CoV-2 infection. Granulocyte-macrophage colony-stimulating factor (GM -CSF) has been proved to be effective in promoting lymphocyte regeneration, but adverse immunological effects have also emerged. This study aim to investigate the effect of GM -CSF on BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration. Cyclophosphamide (CTX) and GM -CSF were used to inhibit and stimulate bone marrow hematopoiesis, respectively. High throughput sequencing was applied to detect the characteristics of BCR CDR3 repertoire in controls, CTX group and GM -CSF group. The white blood cells (WBCs) were quickly reduced (P < 0.05) with lymphocytes decreasing causing by CTX, and the WBCs and lymphocytes returned to the level of controls after GM -CSF treatment. The diversity of BCR heavy chain CDR3 repertoire was also significantly decreased in CTX group. Although there is still a big gap from the controls, the diversity was picked up after GM -CSF treatment. The expression of IGHD01-01, IGHD02-14 and IGHJ04-01 with high-frequency usage regularly and significantly changed in three groups, and many genes with low-frequency usage lost in CTX group and did not reappear in GM -CSF group. Moreover, two shared sequences and accounted for the highest proportion in GM -CSF group have been detected in animal model of chronic lymphocytic leukemia. These results revealed that GM -CSF can partially restore changes in the BCR heavy chain CDR3 repertoire while promoting lymphocyte regeneration, but it may also lead to rearrangement, proliferation and activation of abnormal B cells, which can provide a basis for further study on the adverse immunological effects and mechanism of GM -CSF treatment.


Subject(s)
Cyclophosphamide/adverse effects , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Leukopenia/immunology , Lymphocytes/drug effects , Lymphocytes/immunology , Receptors, Antigen, B-Cell/drug effects , Receptors, Antigen, B-Cell/metabolism , Animals , Complementarity Determining Regions/drug effects , Complementarity Determining Regions/genetics , Complementarity Determining Regions/metabolism , Cyclophosphamide/therapeutic use , Female , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Immunoglobulin Heavy Chains/drug effects , Immunoglobulin Heavy Chains/genetics , Immunoglobulin Heavy Chains/metabolism , Immunoglobulin Joining Region/drug effects , Immunoglobulin Joining Region/metabolism , Immunoglobulin Variable Region/drug effects , Immunoglobulin Variable Region/metabolism , Leukocytes/drug effects , Leukopenia/chemically induced , Leukopenia/drug therapy , Lymphocytes/metabolism , Mice, Inbred BALB C , Receptors, Antigen, B-Cell/immunology
4.
Molecules ; 26(15)2021 Jul 29.
Article in English | MEDLINE | ID: covidwho-1346516

ABSTRACT

We recently developed a molecule (GT-73) that blocked leukocyte transendothelial migration from blood to the peripheral tissues, supposedly by affecting the platelet endothelial cell adhesion molecule (PECAM-1) function. GT-73 was tested in an LPS-induced acute respiratory distress syndrome (ARDS) mouse model. The rationale for this is based on the finding that the mortality of COVID-19 patients is partly caused by ARDS induced by a massive migration of leukocytes to the lungs. In addition, the role of tert-butyl and methyl ester moieties in the biological effect of GT-73 was investigated. A human leukocyte, transendothelial migration assay was applied to validate the blocking effect of GT-73 derivatives. Finally, a mouse model of LPS-induced ARDS was used to evaluate the histological and biochemical effects of GT-73. The obtained results showed that GT-73 has a unique structure that is responsible for its biological activity; two of its chemical moieties (tert-butyl and a methyl ester) are critical for this effect. GT-73 is a prodrug, and its lipophilic tail covalently binds to PECAM-1 via Lys536. GT-73 significantly decreased the number of infiltrating leukocytes in the lungs and reduced the inflammation level. Finally, GT-73 reduced the levels of IL-1ß, IL-6, and MCP-1 in bronchoalveolar lavage fluid (BALF). In summary, we concluded that GT-73, a blocker of white blood cell transendothelial migration, has a favorable profile as a drug candidate for the treatment of ARDS in COVID-19 patients.


Subject(s)
COVID-19/drug therapy , Leukocytes/drug effects , Platelet Endothelial Cell Adhesion Molecule-1/antagonists & inhibitors , Pyrimidines/pharmacology , Respiratory Distress Syndrome/drug therapy , Transendothelial and Transepithelial Migration/drug effects , Animals , COVID-19/pathology , Cell Adhesion/drug effects , Cell Adhesion/immunology , Cell Movement/drug effects , Cytokine Release Syndrome/drug therapy , Cytokines/metabolism , Disease Models, Animal , Female , Humans , Leukocytes/immunology , Lipopolysaccharides/adverse effects , Mice , Mice, Inbred BALB C , Platelet Endothelial Cell Adhesion Molecule-1/immunology , Pyrimidines/chemistry , Respiratory Distress Syndrome/chemically induced , SARS-CoV-2
5.
Adv Mater ; 32(43): e2004901, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-756243

ABSTRACT

The COVID-19 pandemic has taken a significant toll on people worldwide, and there are currently no specific antivirus drugs or vaccines. Herein it is a therapeutic based on catalase, an antioxidant enzyme that can effectively breakdown hydrogen peroxide and minimize the downstream reactive oxygen species, which are excessively produced resulting from the infection and inflammatory process, is reported. Catalase assists to regulate production of cytokines, protect oxidative injury, and repress replication of SARS-CoV-2, as demonstrated in human leukocytes and alveolar epithelial cells, and rhesus macaques, without noticeable toxicity. Such a therapeutic can be readily manufactured at low cost as a potential treatment for COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antioxidants/therapeutic use , Betacoronavirus/drug effects , Catalase/therapeutic use , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Animals , Anti-Inflammatory Agents/pharmacokinetics , Antioxidants/pharmacokinetics , Betacoronavirus/physiology , COVID-19 , Catalase/pharmacokinetics , Cell Line , Coronavirus Infections/metabolism , Coronavirus Infections/virology , Humans , Leukocytes/drug effects , Leukocytes/metabolism , Leukocytes/virology , Macaca mulatta , Mice , Mice, Inbred BALB C , Oxidative Stress/drug effects , Pandemics , Pneumonia, Viral/metabolism , Pneumonia, Viral/virology , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/metabolism , Pulmonary Alveoli/virology , SARS-CoV-2 , Virus Replication/drug effects
6.
Nat Rev Immunol ; 20(10): 633-643, 2020 10.
Article in English | MEDLINE | ID: covidwho-711937

ABSTRACT

Antibody-dependent enhancement (ADE) is a mechanism by which the pathogenesis of certain viral infections is enhanced in the presence of sub-neutralizing or cross-reactive non-neutralizing antiviral antibodies. In vitro modelling of ADE has attributed enhanced pathogenesis to Fcγ receptor (FcγR)-mediated viral entry, rather than canonical viral receptor-mediated entry. However, the putative FcγR-dependent mechanisms of ADE overlap with the role of these receptors in mediating antiviral protection in various viral infections, necessitating a detailed understanding of how this diverse family of receptors functions in protection and pathogenesis. Here, we discuss the diversity of immune responses mediated upon FcγR engagement and review the available experimental evidence supporting the role of FcγRs in antiviral protection and pathogenesis through ADE. We explore FcγR engagement in the context of a range of different viral infections, including dengue virus and SARS-CoV, and consider ADE in the context of the ongoing SARS-CoV-2 pandemic.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antibodies, Viral/administration & dosage , Antibody-Dependent Enhancement/drug effects , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Leukocytes/drug effects , Pneumonia, Viral/drug therapy , Receptors, IgG/immunology , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/biosynthesis , Antibodies, Neutralizing/administration & dosage , Antibodies, Neutralizing/adverse effects , Antibodies, Neutralizing/biosynthesis , Antibodies, Viral/adverse effects , Antibodies, Viral/biosynthesis , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/virology , Dengue/drug therapy , Dengue/immunology , Dengue/virology , Dengue Virus/drug effects , Dengue Virus/immunology , Dengue Virus/pathogenicity , Gene Expression Regulation , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/immunology , Humans , Leukocytes/immunology , Leukocytes/virology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Receptors, IgG/antagonists & inhibitors , Receptors, IgG/genetics , SARS Virus/drug effects , SARS Virus/immunology , SARS Virus/pathogenicity , SARS-CoV-2 , Severe Acute Respiratory Syndrome/drug therapy , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Signal Transduction , Virus Internalization/drug effects
7.
EMBO Mol Med ; 12(8): e12697, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-434202

ABSTRACT

Baricitinib is an oral Janus kinase (JAK)1/JAK2 inhibitor approved for the treatment of rheumatoid arthritis (RA) that was independently predicted, using artificial intelligence (AI) algorithms, to be useful for COVID-19 infection via proposed anti-cytokine effects and as an inhibitor of host cell viral propagation. We evaluated the in vitro pharmacology of baricitinib across relevant leukocyte subpopulations coupled to its in vivo pharmacokinetics and showed it inhibited signaling of cytokines implicated in COVID-19 infection. We validated the AI-predicted biochemical inhibitory effects of baricitinib on human numb-associated kinase (hNAK) members measuring nanomolar affinities for AAK1, BIKE, and GAK. Inhibition of NAKs led to reduced viral infectivity with baricitinib using human primary liver spheroids. These effects occurred at exposure levels seen clinically. In a case series of patients with bilateral COVID-19 pneumonia, baricitinib treatment was associated with clinical and radiologic recovery, a rapid decline in SARS-CoV-2 viral load, inflammatory markers, and IL-6 levels. Collectively, these data support further evaluation of the anti-cytokine and anti-viral activity of baricitinib and support its assessment in randomized trials in hospitalized COVID-19 patients.


Subject(s)
Antiviral Agents/pharmacology , Artificial Intelligence , Azetidines/pharmacology , Betacoronavirus , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sulfonamides/pharmacology , Adult , Aged , Antiviral Agents/pharmacokinetics , Antiviral Agents/therapeutic use , Azetidines/pharmacokinetics , Azetidines/therapeutic use , COVID-19 , Cytokines/antagonists & inhibitors , Drug Evaluation, Preclinical , Drug Repositioning , Female , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Leukocytes/drug effects , Liver , Male , Middle Aged , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Purines , Pyrazoles , SARS-CoV-2 , Spheroids, Cellular/drug effects , Spheroids, Cellular/virology , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use
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