A5078649269- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- HIV/AIDS Research and Interventions
- Pneumocystis jirovecii pneumonia detection and treatment
- SARS-CoV-2 and COVID-19 Research
- Click Chemistry and Applications
- COVID-19 Clinical Research Studies
- Hepatitis C virus research
- Catalytic C–H Functionalization Methods
- Hepatitis B Virus Studies
- Carbohydrate Chemistry and Synthesis
- Photochemistry and Electron Transfer Studies
- Biochemical and Molecular Research
- Urinary Tract Infections Management
- Catalytic Cross-Coupling Reactions
- Animal Virus Infections Studies
- HIV-related health complications and treatments
- Infectious Disease Case Reports and Treatments
- Pediatric Urology and Nephrology Studies
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Viral Infections and Immunology Research
- Protein Degradation and Inhibitors
- Macrophage Migration Inhibitory Factor
- Viral gastroenteritis research and epidemiology
Kumamoto University
2016-2025
Nara Medical University
2019-2024
National Center for Global Health and Medicine
2022-2023
Kumamoto University Hospital
2021-2022
Matsumoto University
2021
Kumamoto Health Science University
2018
National Archives and Records Administration
2014
Okayama University
1998-1999
RIKEN
1999
Tokai University
1998
Dimerization of HIV-1 protease subunits is essential for its proteolytic activity, which plays a critical role in replication. Hence, the inhibition dimerization represents unique target potential intervention HIV-1. We developed an intermolecular fluorescence resonance energy transfer-based HIV-1-expression assay employing cyan and yellow fluorescent protein-tagged monomers. Using this assay, we identified non-peptidyl small molecule inhibitors dimerization. These inhibitors, including...
Abstract While mRNA vaccines against SARS-CoV-2 are exceedingly effective in preventing symptomatic infection, their immune response features remain to be clarified. In the present prospective study, 225 healthy individuals Japan, who received two BNT162b2 doses, were enrolled. Correlates of BNT162b2-elicited SARS-CoV-2-neutralizing activity (50% neutralization titer: NT 50 ; assessed using infectious virions) with various determinants examined and potency sera variants concerns was...
ABSTRACT We examined the intracytoplasmic anabolism and kinetics of antiviral activity against human immunodeficiency virus type 1 (HIV-1) a nucleoside reverse transcriptase inhibitor, 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), which has potent wild-type multidrug-resistant HIV-1 strains. When CEM cells were exposed to 0.1 μM [ 3 H]EFdA or H]3′-azido-2′,3′-dideoxythymidine (AZT) for 6 h, intracellular EFdA-triphosphate (TP) level was 91.6 pmol/10 9 cells, while that AZT 396.5 cells. 10...
We attempted to select HIV-1 variants resistant darunavir (DRV), which potently inhibits the enzymatic activity and dimerization of protease has a high genetic barrier development resistance DRV. conducted selection using mixture 8 highly multi-protease inhibitor (PI)-resistant, DRV-susceptible clinical (HIV-1(MIX)) containing 9 14 PI resistance-associated amino acid substitutions in protease. HIV-1(MIX) became DRV, with 50% effective concentration (EC(50)) ∼333-fold greater than that...
The design, synthesis, and evaluation of a new series hexahydrofuropyranol-derived HIV-1 protease inhibitors are described. We have designed stereochemically defined urethane as the P2-ligand. current ligand is based upon X-ray structure 1a-bound protease. synthesis (3aS,4S,7aR)-hexahydro-2H-furo[2,3-b]pyran-4-ol, (−)-7, was carried out in optically active form. Incorporation this provided inhibitor 35a, which has shown excellent enzyme inhibitory activity antiviral potency. Our...
ABSTRACT We designed, synthesized, and identified GRL-98065, a novel nonpeptidic human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) containing the structure-based designed privileged cyclic ether-derived nonpeptide P2 ligand, 3( R ),3a( S ),6a( )-bis-tetrahydrofuranylurethane (bis-THF), sulfonamide isostere, which is highly potent against laboratory HIV-1 strains primary clinical isolates (50% effective concentration [EC 50 ], 0.0002 to 0.0005 μM) with minimal cytotoxicity...
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,...
Significance Two deadly human retroviruses, T cell leukemia virus type 1 (HTLV-1) and HIV (HIV-1), enter latency in vivo, rendering viral countermeasures ineffective. Recently, novel retroviral genes have been discovered to be expressed from the antisense strand of retroviruses even during latency; they are called genes, including HBZ gene for HTLV-1 ASP HIV-1. We employed RNA-fluorescence situ hybridization technology that messenger RNAs (mRNAs) predominantly localized nucleus infected...
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...
Abstract Drugs that covalently bind to their target molecules form strong and irreversible interactions with each other. Covalent inhibitors have recently attracted attention because of enhanced structural selectivity within the cavity, which results in prolonged interactions, even at low doses. Here, we report ACAi-001 is a human immunodeficiency virus (HIV)-1 capsid (CA)- targeting compound covalent binding CA, estimating long-lasting effects for HIV inhibition. Using library millions...
A healthier HAART: We report the design, synthesis, biological evaluation, and X-ray crystallographic analysis of a new class HIV-1 protease inhibitors. Compound 4 proved to be an extremely potent inhibitor toward various multidrug-resistant variants, representing near 10-fold improvement over darunavir (DRV). also blocked dimerization with at least greater potency than DRV. Detailed facts importance specialist readers are published as "Supporting Information". Such documents peer-reviewed,...
Dimerization of HIV protease is essential for the acquisition protease's proteolytic activity. We previously identified a group dimerization inhibitors, including darunavir (DRV). In present work, we examine whether loss DRV's inhibition activity associated with development DRV resistance. Single amino acid substitutions, I3A, L5A, R8A/Q, L24A, T26A, D29N, R87K, T96A, L97A, and F99A, disrupted dimerization, as examined using an intermolecular fluorescence resonance energy transfer...
The design, synthesis, and biological evaluation of a series HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in active site. Inhibitors 16a 16f showed excellent enzyme inhibitory antiviral activity, although incorporation sulfone functionality resulted decrease potency. Both maintained activity against panel multidrug resistant variants. A...
The design, synthesis, and biological evaluation of a new class HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands variety sulfonamide derivatives P2′ are described. A number ring sizes various substituent effects were investigated to enhance ligand–backbone interactions in active site. Inhibitors 5c 5d this unprecedented 6–5–5 system ligand, an aminobenzothiazole difluorophenylmethyl P1 ligand exhibited exceptional enzyme inhibitory...
Abstract p97/ VCP is an endoplasmic reticulum ( ER )‐associated protein that belongs to the AAA ATP ases associated with diverse cellular activities) ase family. It has a variety of functions including ‐associated degradation, autophagy, and aggresome formation. Recent studies have shown emerging roles its potential as therapeutic target in several cancer subtypes multiple myeloma MM ). We conducted cell‐based compound screen exploit novel small compounds cytotoxic activity cells. Among...
A key transformation in the stereocontrolled synthesis of fucose-containing hexasaccharide 1 is p-methoxybenzyl assisted β-mannosylation.
ABSTRACT We generated a novel nonpeptidic protease inhibitor (PI), GRL-02031, by incorporating stereochemically defined fused cyclopentanyltetrahydrofuran (Cp-THF) which exerted potent activity against wide spectrum of human immunodeficiency virus type 1 (HIV-1) isolates, including multidrug-resistant HIV-1 variants. GRL-02031 was highly laboratory strains and primary clinical subtypes A, B, C, E (50% effective concentration [EC 50 ] range, 0.015 to 0.038 μM), with minimal cytotoxicity...
The structure-based design, synthesis, and biological evaluation of a series nonpeptidic macrocyclic HIV protease inhibitors are described. designed to effectively fill in the hydrophobic pocket S1′−S2′ subsites retain all major hydrogen bonding interactions with protein backbone similar darunavir (1) or inhibitor 2. ring size, effect methyl substitution, unsaturation within structure were assessed. In general, cyclic significantly more potent than their acyclic homologues, saturated rings...
We describe here design, synthesis, and biological evaluation of a series highly potent HIV-1 protease inhibitors containing stereochemically defined unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with variety sulfonamide P2′ ligands. These were designed to enhance the ligand-backbone binding van der Waals interactions active site. A number new ligand, an aminobenzothiazole ligand difluorophenylmethyl P1 displayed very enzyme inhibitory potency also showed...
We report the design, synthesis, biological evaluation, and X-ray crystal structure of a novel inhibitor bound to HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed interact with flap Gly48 carbonyl or amide NH in S2-subsite investigated potential those functionalized ligands combination hydroxyethylsulfonamide isosteres. Inhibitor 26 containing 3-(R)-hydroxyl group on Cp-THF core displayed most potent enzyme inhibitory antiviral activity. Our...