A5053077233- SARS-CoV-2 and COVID-19 Research
- COVID-19 Clinical Research Studies
- Computational Drug Discovery Methods
- Monoclonal and Polyclonal Antibodies Research
- Hepatitis C virus research
- Influenza Virus Research Studies
- Protein Structure and Dynamics
- Antifungal resistance and susceptibility
- Statistical Methods in Clinical Trials
- RNA and protein synthesis mechanisms
- Chemical Synthesis and Analysis
- Statistical Methods and Bayesian Inference
- Viral gastroenteritis research and epidemiology
- Oxidative Organic Chemistry Reactions
- Vanadium and Halogenation Chemistry
- HIV/AIDS drug development and treatment
- Animal Virus Infections Studies
- Cell Image Analysis Techniques
- Microbial Natural Products and Biosynthesis
- Hepatitis B Virus Studies
- interferon and immune responses
- vaccines and immunoinformatics approaches
- Porphyrin Metabolism and Disorders
- Optimal Experimental Design Methods
- Synthesis and Catalytic Reactions
Janssen (Belgium)
2011-2025
University of Antwerp
2024
Janssen (United States)
2024
Janssen (United Kingdom)
2020
Johnson & Johnson (United States)
2015
KU Leuven
2014
Hasselt University
2014
Maastricht University
2014
Ghent University
2008-2009
Vrije Universiteit Brussel
2009
Influenza therapeutics with new targets and mechanisms of action are urgently needed to combat potential pandemics, emerging viruses, constantly mutating strains in circulation. We report here on the design structural characterization potent peptidic inhibitors influenza hemagglutinin. The peptide was based complementarity-determining region loops human broadly neutralizing antibodies against hemagglutinin (FI6v3 CR9114). optimized peptides exhibit nanomolar affinity neutralization A group 1...
ObjectivesGiven the high need and absence of specific antivirals for treatment COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives.MethodsPrezcobix/Rezolsta is a fixed-dose combination 800 mg HIV inhibitor darunavir (DRV) 150 cobicistat, CYP3A4 inhibitor, which indicated in with other antiretroviral agents infection. There currently no...
Recent characterization of broadly neutralizing antibodies (bnAbs) against influenza virus identified the conserved hemagglutinin (HA) stem as a target for development universal vaccines and therapeutics. Although several bnAbs are being evaluated in clinical trials, generally unsuited oral delivery. Guided by structural knowledge interactions mechanism anti-stem bnAb CR6261, we selected optimized small molecules that mimic functionality. Our lead compound neutralizes A group 1 viruses...
Abstract The membrane (M) protein of betacoronaviruses is well conserved and has a key role in viral assembly 1,2 . Here we describe the identification JNJ-9676, small-molecule inhibitor targeting coronavirus M protein. JNJ-9676 demonstrates vitro nanomolar antiviral activity against SARS-CoV-2, SARS-CoV sarbecovirus strains from bat pangolin zoonotic origin. Using cryogenic electron microscopy (cryo-EM), determined binding pocket formed by transmembrane domains dimer. Compound stabilized...
Abstract Although vaccination campaigns are currently being rolled out to prevent coronavirus disease (COVID‐19), antivirals will remain an important adjunct vaccination. Antivirals against coronaviruses do not exist, hence global drug repurposing efforts have been carried identify agents that may provide clinical benefit patients with COVID‐19. Itraconazole, antifungal agent, has reported activity animal coronaviruses. Using cell‐based phenotypic assays, the in vitro antiviral of...
The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as new inhibitor NS5B RNA-dependent RNA polymerase, displaying an EC(50) 7.3 μM measured Huh7-Rep cell line no associated cytotoxicity (CC(50) > 98.4 μM). Computational...
Abstract Although vaccines are currently used to control the coronavirus disease 2019 (COVID‐19) pandemic, treatment options urgently needed for those who cannot be vaccinated and future outbreaks involving new severe acute respiratory syndrome virus 2 (SARS‐CoV‐2) strains or coronaviruses not covered by current vaccines. Thus far, few existing antivirals known effective against SARS‐CoV‐2 clinically successful COVID‐19. As part of an immediate response COVID‐19 a high‐throughput, high...
Abstract Background Heart rate (HR) tracking with wrist-worn photoplethysmography (PPG)-based monitors could assist in following up physical activity (PA) cardiac patients, but the accuracy can vary, particularly during intensive exercise. Currently, limited research has investigated influence of technical factors such as device positioning, sensor cleanliness and interference from body hair, on PPG accuracy. Purpose This study assessed whether adjustments improve PPG-based HR patients low...
We present a novel approach for enhancing the diversity of chemical library rooted on theory wisdom crowds. Our was motivated by desire to tap into collective experience our global medicinal chemistry community and involved four basic steps: (1) Candidate compounds acquisition were screened using various structural property filters in order eliminate clearly nondrug-like matter. (2) The remaining clustered together with in-house collection fingerprint-based clustering algorithm that...
In the search for novel influenza inhibitors we evaluated 7-fluoro-substituted indoles as bioisosteric replacements 7-azaindole scaffold of Pimodivir, a PB2 (polymerase basic protein 2) inhibitor currently in clinical development. Specifically, 5,7-difluoroindole derivative 11a was identified potent and metabolically stable inhibitor. demonstrated favorable oral pharmacokinetic profile vivo efficacy mice. addition, it found that not at risk metabolism via aldehyde oxidase, an advantage over...
Abstract Given the high need and absence of specific antivirals for treatment COVID-19 (the disease caused by severe acute respiratory syndrome-associated coronavirus-2 [SARS-CoV-2]), human immunodeficiency virus (HIV) protease inhibitors are being considered as therapeutic alternatives. Prezcobix/Rezolsta is a fixed-dose combination 800 mg HIV inhibitor darunavir (DRV) 150 cobicistat, CYP3A4 inhibitor, which indicated in with other antiretroviral agents infection. There currently no...
<title>Abstract</title> The membrane (M) protein of betacoronaviruses is well-conserved and plays a key role in viral assembly. Here, we describe the discovery JNJ-9676, novel small molecule targeting coronaviral (CoV) M protein. JNJ-9676 demonstrates <italic>in vitro</italic> nanomolar antiviral activity against SARS-CoV2, SARS-CoV, sarbecovirus strains from bat pangolin zoonotic origin. Using cryogenic electron microscopy, determined binding pocket protein's transmembrane domain. Compound...
Abstract Protocols for the design of kinase‐focused compound libraries are presented. Kinase‐focused can be differentiated based on goal. Depending whether library should a discovery specific one particular kinase, general multiple distinct kinase projects, or even phenotypic screening, there exists today variety in silico methods to candidate libraries. We address following scenarios: 1) Datamining SAR databases and focused vendor catalogues; 2) Predictions virtual screening; 3)...
In silico binding site location and pose prediction for a molecule targeted at large protein surface is challenging task. We report blind test with two peptidomimetic molecules that bind the flu virus hemagglutinin (HA) antigen, JNJ7918 JNJ4796 (recently disclosed in van Dongen et al., Science, 2019, 363). Tests series of conventional approaches such as rigid (receptor) docking against available X-ray crystal structures or an ensemble generated by quick methodologies (NMA, homology modeling)...
Abstract Human spermine oxidase (hSMOX) plays a central role in polyamine catabolism. Due to its association with several pathological processes, including inflammation and cancer, hSMOX has garnered interest as possible therapeutic target. Therefore, determination of the structure is an important step enable drug discovery validate Using insights from hydrogen/deuterium exchange mass spectrometry (HDX-MS), we engineered construct obtain first crystal bound known inhibitor MDL72527 at 2.4 Å...
The recent pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) posed a major threat to global health. Although the World Health Organization ended public health emergency status, antiviral drugs are needed address new variants of SARS-CoV-2 and future pandemics. To identify novel broad-spectrum drugs, we developed high-content imaging platform compatible with high-throughput screening. is broadly applicable as it can be adapted include various cell types, viruses,...
N-(1-Aryl-2,2-dichloropent-4-enylidene)amines were efficiently transformed into 5-bromomethyl-1-pyrrolinium bromides via electrophile-induced bromocyclization. The latter pyrrolinium salts converted novel 5-alkoxymethyl-2-aryl-3-chloropyrroles by reaction with alkoxides in the corresponding alcohol or THF. This chemistry clearly deviates from γ,δ-unsaturated α,α-dialkylaldimines under similar conditions. Furthermore, treatment of sodium hydroxide water afforded a new entry 2-aroylpyrroles an...
Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. We propose a method to quantify these qualitative assessments using hierarchical models. However, with most commonly available computing resources, high dimensionality vectors fixed effects and correlated responses renders maximum likelihood unfeasible this scenario. devise reliable procedure tackle problem show, theoretical arguments simulations, that new methodology...
Expert opinion plays an important role when choosing clusters of chemical compounds for further investigation. Often, the process by which are assigned to experts evaluation, so-called selection process, and qualitative ratings given (chosen/not chosen) need be jointly modeled avoid bias. This approach is referred as joint modeling approach. However, misspecifying model may impact estimation inferences on parameters in rating model, most scientific interest. We propose incorporate into...
The ongoing COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is partly under control vaccination. However, highly potent and safe antiviral drugs for SARS-CoV-2 are still needed to avoid development of COVID-19. We report the discovery a small molecule, Z-Tyr-Ala-CHN2, which was identified in cell-based screen. molecule exerts sub-micromolar activity against SARS-CoV-2, SARS-CoV-1, human 229E. Time-of-addition studies reveal that Z-Tyr-Ala-CHN2 acts...
Expert opinion plays an important role when selecting promising clusters of chemical compounds in the drug discovery process. Indeed, experts can qualitatively assess potential each cluster, and with appropriate statistical methods, these qualitative assessments be quantified into a success probability for them. However, one crucial element often overlooked is procedure by which are assigned to/selected evaluation. In present work, impact such may have on analysis entire evaluation process...
Abstract Background Heart rate (HR) tracking by wrist-worn devices using photoplethysmography (PPG) could assist in continuously following up physical activity. However, the accuracy can be impacted (motion) artefacts. Machine learning models help to recognise artefacts PPG-based HR data. The choice of classifier these machine is a determing factor for task performance model. Purpose This study evaluates and determines optimal new learning-based approach enhance reliability artefact...