A5023193233- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- Respiratory viral infections research
- HIV Research and Treatment
- Catalytic Cross-Coupling Reactions
- Mosquito-borne diseases and control
- Hepatitis B Virus Studies
- Synthesis and bioactivity of alkaloids
- Catalytic C–H Functionalization Methods
- Synthesis and Catalytic Reactions
- Malaria Research and Control
- Viral Infections and Vectors
- Biochemical and Molecular Research
- Chemical Synthesis and Analysis
- Immune Response and Inflammation
- Viral gastroenteritis research and epidemiology
- Synthesis and pharmacology of benzodiazepine derivatives
- Monoclonal and Polyclonal Antibodies Research
- Synthesis and biological activity
- Pneumonia and Respiratory Infections
- Cancer therapeutics and mechanisms
- Synthesis and Reactivity of Heterocycles
- Pneumocystis jirovecii pneumonia detection and treatment
- Influenza Virus Research Studies
- Click Chemistry and Applications
Janssen (Belgium)
2016-2025
Johnson & Johnson (United States)
2020
Boehringer Ingelheim (Canada)
2010
University of Antwerp
1999-2004
University of Massachusetts Chan Medical School
2004
University of Liège
2002
Rega Institute for Medical Research
2002
Inserm
2002
Aligarh Muslim University
2002
Abstract Dengue is a major health threat and the number of symptomatic infections caused by four dengue serotypes estimated to be 96 million 1 with annually around 10,000 deaths 2 . However, no antiviral drugs are available for treatment or prophylaxis dengue. We recently described interaction between non-structural proteins NS3 NS4B as promising target development pan-serotype virus (DENV) inhibitors 3 Here we present JNJ-1802—a highly potent DENV inhibitor that blocks NS3–NS4B within viral...
The screening of known HIV-1 protease inhibitors against a panel multi-drug-resistant viruses revealed the potent activity TMC126 on drug-resistant mutants. In comparison to amprenavir, improved affinity is largely result one extra hydrogen bond backbone protein in P2 pocket. Modification substitution pattern phenylsulfonamide P2' substituent created an interesting SAR, with close analogue TMC114 being found have similar antiviral mutant and wild-type viruses. X-ray thermodynamic studies...
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...
Dengue is a global public health threat, with about half of the world's population at risk contracting this mosquito-borne viral disease. Climate change, urbanization, and travel accelerate spread dengue virus (DENV) to new areas, including southern parts Europe US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment available. Here, we report discovery JNJ-1802 as potent, pan-serotype DENV inhibitor (EC50's ranging from 0.057 11 nM against four serotypes)....
On the basis of original lead neocryptolepine or 5-methyl-5H-indolo[2,3-b]quinoline, an alkaloid from Cryptolepis sanguinolenta, derivatives were prepared using a biradical cyclization methodology. Starting easily accessible educts, this approach allowed synthesis hitherto unknown compounds with varied substitution pattern. As result steric hindrance, preferential formation 3-substituted isomers over 1-substituted was observed when cyclizing...
The respiratory syncytial virus polymerase complex, consisting of the (L) and phosphoprotein (P), catalyzes nucleotide polymerization, cap addition, methylation via RNA dependent polymerase, capping, Methyltransferase domains on L. Several nucleoside non-nucleoside inhibitors have been reported to inhibit this but structural details exact inhibitor-polymerase interactions lacking. Here, we report a inhibitor JNJ-8003 with sub-nanomolar inhibition potency in both antiviral assays. Our 2.9 Å...
Purine-β-lactam chimera were prepared as a novel class of hybrid systems through N-alkylation 6-benzylamino- or 6-benzyloxypurine with (ω-haloalkyl)-β-lactams, followed by reductive ring opening the β-lactam LiEt(3)BH to provide an entry into purine-aminopropanol hybrids. Both new types assessed for their antiviral activity and cytotoxicity, resulting in identification eight purine-β-lactam hybrids two promising lead structures.
Respiratory syncytial virus (RSV) remains a public health burden due to unmet therapeutic needs. We recently reported the discovery of non-nucleoside inhibitor RSV polymerase and characterized its binding novel pocket within capping domain polymerase. Here, we describe our strategy diversify chemical matter targeting this site by screening DNA-encoded libraries, leading potent series molecules that inhibits polymerase's biochemical activity, as well viral replication in cells. Structural...
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...
The limited efficacy, in particular against the genotype 1 virus, as well variety of side effects associated with current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured Huh7-replicon cell line, no apparent cytotoxicity (CC50 > 98.4 μM). Confirming...
Human immunodeficiency virus type 1 (HIV-1) protease has been continuously evolving and developing resistance to all of the inhibitors. This requires development new inhibitors that bind in a novel fashion. Most are on market peptidomimetics, where conserved water molecule mediates hydrogen bonding interactions between flaps protease. Recently class inhibitors, lysine sulfonamides, was developed combat resistant variants HIV Here we report crystal structure sulfonamide. inhibitor binds...
ABSTRACT TMC310911 is a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI) structurally closely related to darunavir (DRV) but with improved virological characteristics. has potent activity against wild-type (WT) HIV-1 (median 50% effective concentration [EC 50 ], 14 nM) and wide spectrum of recombinant clinical isolates, including multiple-PI-resistant strains decreased susceptibility currently approved PIs (fold change [FC] in EC , >10). For panel 2,011 isolates...
A novel series of 2,4-diaminoquinazolines was identified as potent dual Toll-like receptor (TLR) 7 and 8 agonists with reduced off-target activity. The stereochemistry the amino alcohol found to influence TLR7/8 selectivity ( R) isomer resulting in selective TLR8 agonism. Lead optimization toward a agonist afforded S)-3-((2-amino-8-fluoroquinazolin-4-yl)amino)hexanol 31 analog, being structurally different from previously described McGowan J. Med. Chem. 2016 , 59 7936 ). Pharmacokinetic...
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...
Respiratory syncytial virus (RSV) is a seasonal that infects the lungs and airways of 64 million children adults every year. It major cause acute lower respiratory tract infection associated with significant morbidity mortality. Despite large medical economic burden, treatment options for RSV-associated bronchiolitis pneumonia are limited mainly consist supportive care. This publication covers medicinal chemistry efforts resulting in identification JNJ-53718678, an orally bioavailable RSV...
Respiratory syncytial virus (RSV) is a major cause of hospitalization in infants, the elderly, and immune-compromised patients. While half-life extended monoclonal antibody 2 vaccines have recently been approved for infants respectively, options to prevent disease patients are still needed. Here, we describe spiro-azetidine oxindoles as small molecule RSV entry inhibitors displaying favorable potency, developability attributes, long-acting PK when injected an aqueous suspension, suggesting...
Respiratory syncytial virus (RSV) is an RNA infecting the upper and lower respiratory tract recognized as a major health threat, particularly to older adults, immunocompromised individuals, young children. Around 64 million children adults are infected every year worldwide. Despite two vaccines new generation monoclonal antibody recently approved, no effective antiviral treatment available. In this manuscript, we present medicinal chemistry efforts resulting in identification of compound 28...
JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors HCV NS5B RNA-dependent RNA polymerase (RdRp). In Huh-7 genotype (GT) 1b replicon-containing cell line 9 devoid any anti-HCV activity, an observation attributable inefficient prodrug metabolism was found be CYP3A4-dependent. contrast, in vitro incubation primary human hepatocytes well pharmacokinetic evaluation thereof...
In the absence of any approved dengue-specific treatment, discovery and development a novel small-molecule antiviral for prevention or treatment dengue are critical. We previously reported identification series 3-acyl-indole derivatives as potent pan-serotype virus inhibitors. herein describe our optimization efforts toward preclinical candidates 24a 28a with improved coverage (EC50's against four DENV serotypes ranging from 0.0011 to 0.24 μM 0.00060 0.084 28a), chiral stability, oral...