A5012018663- SARS-CoV-2 and COVID-19 Research
- HIV/AIDS drug development and treatment
- Hepatitis B Virus Studies
- Hepatitis C virus research
- COVID-19 Clinical Research Studies
- HIV Research and Treatment
- Computational Drug Discovery Methods
- Bacteriophages and microbial interactions
- Systemic Sclerosis and Related Diseases
- HIV-related health complications and treatments
- Synthesis and biological activity
- Dermatologic Treatments and Research
- COVID-19 Impact on Reproduction
- Lymphatic System and Diseases
- Bacillus and Francisella bacterial research
- Click Chemistry and Applications
- Cytomegalovirus and herpesvirus research
- SARS-CoV-2 detection and testing
- interferon and immune responses
- Liver Disease Diagnosis and Treatment
- Endoplasmic Reticulum Stress and Disease
- Drug Transport and Resistance Mechanisms
- Phagocytosis and Immune Regulation
- Tuberculosis Research and Epidemiology
- Neonatal Health and Biochemistry
National Center for Global Health and Medicine
2015-2024
Kumamoto University
2009-2023
Center for Global Health
2017-2023
Nagoya City University
2021
Chulalongkorn University
2021
Tokushima University
2021
National Institutes of Health
2021
European Foundation for the Study of Chronic Liver Failure
2021
Abstract Except remdesivir, no specific antivirals for SARS-CoV-2 infection are currently available. Here, we characterize two small-molecule-compounds, named GRL-1720 and 5h, containing an indoline indole moiety, respectively, which target the main protease (M pro ). We use VeroE6 cell-based assays with RNA-qPCR, cytopathic assays, immunocytochemistry show both compounds to block infectivity of EC 50 values 15 ± 4 4.2 0.7 μM respectively. Remdesivir permitted viral breakthrough at high...
Recent accumulating evidence indicates a crucial involvement of macrophage lineage in the pathogenesis systemic sclerosis (SSc). To analyze assembly monocyte/macrophage population, we evaluated expression CD163 and CD204 various activated markers, inflammatory cells skin peripheral blood mononuclear (PBMCs) derived from patients with SSc.Skin biopsy specimens 6 healthy controls 10 SSc (7 limited cutaneous 3 diffuse SSc) were analyzed by immunohistochemistry using monoclonal antibody against...
Abstract COVID-19 caused by SARS-CoV-2 has continually been serious threat to public health worldwide. While a few anti-SARS-CoV-2 therapeutics are currently available, their antiviral potency is not sufficient. Here, we identify two orally available 4-fluoro-benzothiazole-containing small molecules, TKB245 and TKB248, which specifically inhibit the enzymatic activity of main protease (M pro ) significantly more potently block infectivity replication various strains than nirmatrelvir,...
Abstract While there are various attempts to administer COVID-19-convalescent plasmas SARS-CoV-2-infected patients, neither appropriate approach nor clinical utility has been established. We examined the presence and temporal changes of neutralizing activity IgG fractions from 43 using cell-based assays with multiple endpoints. 27 cases (62.8%) had significant moderately potently inhibited SARS-CoV-2 infection in assays; however, no detectable was found 16 (37.2%). Approximately half...
The main protease (Mpro) of SARS-CoV-2 is an attractive target for the development drugs to treat COVID-19. Here, we report design, synthesis, and structure-activity relationship (SAR) studies highly potent Mpro inhibitors including TKB245 (5)/TKB248 (6). Since have previously developed (3) (4), several hybrid molecules these previous compounds combined with nirmatrelvir (1) were designed synthesized. Compounds such as (5) TKB248 (6), containing a 4-fluorobenzothiazole moiety at P1' site,...
Certain nucleoside/nucleotide reverse transcriptase (RT) inhibitors (NRTIs) are effective against human immunodeficiency virus type 1 (HIV‐1) and hepatitis B (HBV). However, both viruses often acquire NRTI resistance, making it crucial to develop more‐potent agents that offer profound viral suppression. Here, we report 4′‐C‐cyano‐2‐amino‐2′‐deoxyadenosine (CAdA) is a novel, highly potent inhibitor of HBV (half maximal inhibitory concentration [IC 50 ] = 0.4 nM) HIV‐1 (IC nM). In contrast,...
Antiretroviral therapy for HIV-1 infection/AIDS has significantly extended the life expectancy of HIV-1-infected individuals and reduced transmission at very high rates. However, certain who initially achieve viral suppression to undetectable levels may eventually suffer treatment failure mainly due adverse effects emergence drug-resistant variants. Here, we report GRL-142, a novel protease inhibitor containing an unprecedented 6-5-5-ring-fused crown-like tetrahydropyranofuran, which...
SARS-CoV-2-BA.4/5-adapted-bivalent-BNT162b2-vaccine (bvBNT), developed in response to the recent emergence of immune-evasive Omicron-variants, has been given individuals who completed at least 2-doses monovalent-BNT162b2-vaccine (mvBNT). In present cohort study, we evaluated neutralization-titers (NT50s) against Wuhan-strain (SCoV2Wuhan) and Omicron-sublineages including BA.2/BA.5/BQ.1.1/XBB/XBB.1.5, vaccine-elicited S1-binding-IgG sera from participants-vaccinated with 5th-bvBNT following...
Despite various attempts to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients with COVID-19 convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration highly neutralizing plasma (
Potent and biostable inhibitors of the main protease (Mpro) SARS-CoV-2 were designed synthesized based on an active hit compound 5h (2). Our strategy was not only introduction fluorine atoms into inhibitor molecule for increase binding affinity pocket Mpro cell membrane permeability but also replacement digestible amide bond by a surrogate structure to biostability compounds. Compound 3 is highly potent blocks infection in vitro without viral breakthrough. The derivatives, which contain...
While certain nucleos(t)ide reverse transcriptase inhibitors (NRTIs) are efficacious in treating HBV infection, their effects yet to be optimized and the emergence of NRTI-resistant variants is an issue because requirement for lifelong treatment. The development agents that more profoundly suppress wild-type drug-resistant HBVs, have a long-acting effect, crucial improve patient outcomes.Herein, we synthesized novel 4'-modified NRTI termed E-CFCP. We tested its anti-HBV activity vitro,...
We designed, synthesized, and characterized a novel nucleoside analog, (1S,3S,5S)-3-(2-amino-6-oxo-1,6-dihydro-9H-purin-9-yl)-5-hydroxy-1-(hydroxymethyl)-2-methylene-cyclopentanecarbonitrile, or 4'-cyano-methylenecarbocyclic-2'-deoxyguanosine (CMCdG), evaluated its anti-hepatitis B virus (anti-HBV) activity, safety, related features. CMCdG's in vitro activity was determined using quantitative PCR Southern blotting assays, cytotoxicity with...
Abstract The persistence of covalently closed circular DNA (cccDNA) poses a major obstacle to curing chronic hepatitis B (CHB). Here, we used droplet digital PCR (ddPCR) for cccDNA quantitation. cccDNA-specific ddPCR showed high accuracy with the dynamic range detection from 10 1 5 copies/assay. had higher sensitivity, specificity and precisely than qPCR. results correlated closely serum HB core-related antigen surface (HBsAg) in 24 HBV-infected human-liver-chimeric mice (PXB-mice). We...
In the development of anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) drugs, its main protease (Mpro), which is an essential enzyme for viral replication, a promising target. To date, Mpro inhibitors, nirmatrelvir and ensitrelvir, have been clinically developed by Pfizer Inc. Shionogi & Co., Ltd., respectively, as orally administrable drugs to treat disease 2019 (COVID-19). We also several potent inhibitors SARS-CoV-2 that include compounds 4, 5, TKB245 (6), TKB248 (7),...
Cellular senescence is a cellular state with broad spectrum of age-related physiological conditions that can be affected by various infectious diseases and treatments. Therapy hepatitis B virus (HBV) infection nucleos(t)ide analogs [NA(s)] well established benefits many HBV-infected patients, but requires long-term, perhaps lifelong, medication. In addition to the effects HBV infection, NA administration on hepatocellular are still unclear. This study investigated how treatment influence in...
Nuclear localization signal (NLS) of HIV-1 integrase (IN) is implicated in nuclear import preintegration complex (PIC). Here, we established a multiclass drug-resistant variant (HIV
Abstract 2,6‐Diaminopurine and guanine 2′‐deoxynucleosides substituted with a fluoromethyl, methyl, vinyl, ethyl, or azido group at the C ‐4’ position of sugar moiety 1–10 were synthesized their activity against HIV HBV determined. 4′‐Fluoromethyl 4′‐methyl derivatives 1 2 , respectively, by glycosidation 4′‐substituted sugars 11 12 using 2,6‐diaminopurine, followed deoxygenation 2′‐hydroxyl group. 4′‐Vinyl analog 3 was from 4′‐hydroxymethylnucleoside 19 4′‐ethyl derivative 4 obtained...
The hiPSC-derived spheroids we generated are more expensive to obtain than the human cell lines currently available for anti-SARS-CoV-2 drug evaluation, such as Calu-3 cells; however, have better infection susceptibility existing lines. Although cognizant that there lung (and colonic) organoid models study of SARS-CoV-2, production those organoids is greatly costly and time consuming generation iPSC-derived spheroid cells.
The earliest clinical symptoms of systemic sclerosis (SSc) relate to disturbances in the peripheral vascular system. However, detailed examination microcirculation including lymphatics skin patients with SSc has not been reported. aim our study was examine expression patterns endothelial growth factor receptor (VEGFR)-1, VEGFR-2, VEGFR-3 and lymphatic cell marker D2-40 patients. Skin biopsy specimens from nine were analysed by immunohistochemistry using antibodies against VEGFR-1, protein....
ABSTRACT Despite various attempts to treat SARS-CoV-2-infected patients with COVID-19-convalescent plasmas, neither appropriate approach nor clinical utility has been established. We examined the efficacy of administration highly-neutralizing plasma ( hn -plasmas) and such plasma-derived IgG using Syrian hamster COVID-19 model. Two -plasmas, which were in best 1% 340 neutralizing-activity-determined convalescent samples, intraperitoneally administered hamsters, resulting significant...