A5101701390- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- Biochemical and Molecular Research
- SARS-CoV-2 and COVID-19 Research
- HIV Research and Treatment
- Hepatitis B Virus Studies
- interferon and immune responses
- Viral Infections and Immunology Research
- Computational Drug Discovery Methods
- Liver Disease Diagnosis and Treatment
- Bacteriophages and microbial interactions
- Virus-based gene therapy research
- RNA and protein synthesis mechanisms
- Cytomegalovirus and herpesvirus research
- Mosquito-borne diseases and control
- Inflammatory mediators and NSAID effects
- Thyroid Disorders and Treatments
- Neuroendocrine Tumor Research Advances
- Drug Transport and Resistance Mechanisms
- Liver Diseases and Immunity
- Pneumocystis jirovecii pneumonia detection and treatment
- COVID-19 Clinical Research Studies
- CAR-T cell therapy research
- Hepatocellular Carcinoma Treatment and Prognosis
- Growth Hormone and Insulin-like Growth Factors
Janssen (United States)
2019-2020
Johnson & Johnson (United States)
2018
Sunesis (United States)
2016
Roche (United States)
2010
La Roche College
2009
Architecture et Fonction des Macromolécules Biologiques
2008
McGill University
2006
Aix-Marseille Université
2004
Centre National de la Recherche Scientifique
2004
The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with >20× increase 50% effective...
Abstract The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with > 20x increase EC 50...
The 3-chymotrypsin-like cysteine protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered a major target for the discovery direct antiviral agents. We previously reported evaluation SARS-CoV-2 3CLpro inhibitors in novel self-assembled monolayer desorption ionization mass spectrometry (SAMDI-MS) enzymatic assay (Gurard-Levin et al., 2020). was further improved by adding rhinovirus HRV3C to same well as enzyme. High substrate specificity each enzyme...
ABSTRACT We have discovered a novel class of human immunodeficiency virus (HIV) reverse transcriptase (RT) inhibitors that block the polymerization reaction in mode distinct from those nucleoside or nucleotide RT (NRTIs) and nonnucleoside (NNRTIs). For this indolopyridone compounds, steady-state kinetics revealed competitive inhibition with respect to substrate. Despite substantial structural differences classical chain terminators natural nucleotides, these data suggest binding site HIV may...
Chronic hepatitis B (CHB) represents a significant unmet medical need with few options beyond lifelong treatment nucleoside analogues, which rarely leads to functional cure. Novel agents that reduce levels of HBV DNA, RNA and other viral antigens could lead better outcomes. The capsid assembly modulator (CAM) class compounds an important modality for chronic suppression improve cure rates, either alone or in combination.
Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some hypothesized that the active metabolites toxic analogs, triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting transcription protein synthesis. Others proposed prodrug moiety released from might instead cause toxicity. Here, we report effects several clinically relevant structurally diverse...
We report the synthesis and biological evaluation of a series 4'-fluoro-2'- C-substituted uridines. Triphosphates uridine analogues exhibited potent inhibition hepatitis C virus (HCV) NS5B polymerase with IC50 values as low 27 nM. In an HCV subgenomic replicon assay, phosphoramidate prodrugs these demonstrated very activity EC50 20 A lead compound AL-335 (53) high levels nucleoside triphosphate in vitro primary human hepatocytes Huh-7 cells well dog liver following single oral dose. Compound...
IL-2-inducible T cell kinase plays an essential role in receptor signaling and is considered a drug target for the treatment of Th2-mediated inflammatory diseases. By applying high-throughput protein engineering crystallization, we have determined X-ray crystal structures complex with its selective inhibitor BMS-509744 broad-spectrum inhibitors sunitinib RO5191614. Sunitinib uniquely stabilizes helix C-in conformation by inducing side chain conformational changes ATP-binding site. This...
Chronic hepatitis C (CHC) is a major liver disease caused by the virus. The current standard of care for CHC can achieve cure rates above 95%; however, drugs in use are administered period 8-16 weeks. A combination safe and effective with shorter treatment highly desirable. We report synthesis biological evaluation series 2',3'- 2',4'-substituted guanosine nucleotide analogues. Their triphosphates exhibited potent inhibition HCV NS5B polymerase IC50 as low 0.13 μM. In replicon assay,...
A class of amino acid substitutions in drug-resistant HIV-1 reverse transcriptase (RT) is responsible for the selectively impaired incorporation nucleotide analog inhibitor into DNA. We have shown previously that alpha-boranophosphate nucleoside analogs suppress RT-mediated resistance when catalytic rate drug such as case K65R and dideoxy (dd)NTPs, Q151M toward AZTTP ddNTPs. Here, we extend this property to BH3-d4TTP BH3-3TCTP their clinically relevant mutants M184V, respectively....
Human respiratory syncytial virus (RSV) is a negative-sense RNA and significant cause of infection in infants the elderly. No effective vaccines or antiviral therapies are available for treatment RSV. ALS-8176 first-in-class nucleoside prodrug inhibitor RSV replication currently under clinical evaluation. ALS-8112, parent molecule ALS-8176, undergoes intracellular phosphorylation, yielding active 5′-triphosphate metabolite. The host kinases responsible this conversion not known. Therefore,...
In the treatment of HIV, loose active site HIV-1 reverse transcriptase (RT) allows numerous nucleotide analogues to act as proviral DNA 'chain-terminators'. Acyclic phosphonate (ANPs) represent a particular class analogue that does not possess ribose moiety. The structural basis for their substrate efficiency regarding viral polymerases is poorly understood.Pre-steady-state kinetics on RT together with molecular modelling, were used evaluate relative characteristics both initial binding and...
Current treatments for human immunodeficiency virus (HIV) infection target viral enzymes such as the protease and reverse transcriptase (RT), well envelope glycoprotein gp41. RT inhibitors include nucleoside nonnucleoside that bind to distinct sites within polymerase. Zidovudine, stavudine, zalcitabine, didanosine, lamivudine, abacavir, tenofovir emtricitabine are converted active triphosphate analogues incorporated into nascent DNA in reactions catalyzed by HIV RT. Since lack 3-OH group...
Agonists of thyroid hormone receptor β (THR-β) decreased LDL cholesterol (LDL-C) and triglyceride (TG) levels in human clinical trials for patients with dyslipidemia. The authors present the highly potent selective compound ALG-055009 (
Abstract There is an urgent need for antivirals targeting the SARS-CoV-2 virus to fight current COVID-19 pandemic. The main protease (3CLpro) represents a promising target antiviral therapy. lack of selectivity some reported 3CLpro inhibitors, specifically versus cathepsin L, raises potential safety and efficacy concerns. ALG-097111 potently inhibited (IC 50 = 7 nM) without affecting activity human L > 10 μM). When was dosed in hamsters challenged with SARS-CoV-2, robust significant 3.5...