A5025082607- SARS-CoV-2 and COVID-19 Research
- Respiratory viral infections research
- Tryptophan and brain disorders
- Computational Drug Discovery Methods
- HIV/AIDS drug development and treatment
- Cholinesterase and Neurodegenerative Diseases
- Viral gastroenteritis research and epidemiology
- Bipolar Disorder and Treatment
- Influenza Virus Research Studies
- Phosphodiesterase function and regulation
- Lipoproteins and Cardiovascular Health
- HIV Research and Treatment
- COVID-19 Clinical Research Studies
- Neonatal Respiratory Health Research
- Biosimilars and Bioanalytical Methods
- Biochemical and Molecular Research
- Neuropeptides and Animal Physiology
- Bacteriophages and microbial interactions
- Chemical synthesis and alkaloids
- Peptidase Inhibition and Analysis
- Pharmacological Receptor Mechanisms and Effects
- Viral Infections and Outbreaks Research
- 14-3-3 protein interactions
- Chemical Synthesis and Analysis
- Amino Acid Enzymes and Metabolism
Janssen (United States)
2022-2025
Johnson & Johnson (United States)
2023-2025
Springhouse
2023-2025
United States Military Academy
2005-2021
Janssen (Switzerland)
2021
Quantitative BioSciences
2021
Merck & Co., Inc., Rahway, NJ, USA (United States)
2020-2021
Target (United States)
2017
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 HIV/AIDS continues to be a menace public health. Several drugs currently on the market have successfully improved ability manage viral burden in infected patients. However, new are needed combat rapid emergence of mutated forms virus that resistant existing therapies. Currently, approved target three four major enzyme activities encoded by critical HIV life cycle. Although number inhibitors RNase H activity been reported, few inhibit directly engaging active site. Here, we describe...
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...
The unique S28 family of proteases is comprised the carboxypeptidase PRCP and aminopeptidase DPP7. structural basis different substrate specificities two enzymes not understood nor has structure fold been described. experimentally phased 2.8 Å crystal presented for human PRCP. contains an α/β hydrolase domain harboring catalytic Asp-His-Ser triad a novel helical that caps active site. Structural comparisons with prolylendopeptidase DPP4 identify S1 proline binding site A structure-based...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as a target of significant interest to the field cancer immunotherapy, upregulation IDO1 in certain cancers been linked host immune evasion and poor prognosis for patients. In particular, inhibition is combination therapy with checkpoint inhibition. Through an Automated Ligand Identification System (ALIS) screen, diamide class compounds was identified promising lead IDO1. While hit 1 possessed attractive cell-based potency, it suffered from...
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present discovery class inhibitors based on 2-pyridinone core MK-0536. These efforts led to identification two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles support once-daily human dose prediction. Dose escalating PK studies in dog...
Indoleamine-2,3-dioxygenase-1 (IDO1) has emerged as an attractive target for cancer immunotherapy. An automated ligand identification system screen afforded the tetrahydroquinoline class of novel IDO1 inhibitors. Potency and pharmacokinetic (PK) were key issues with this compounds. Structure-based drug design strategic incorporation polarity enabled rapid improvement on potency, solubility, oxidative metabolic stability. Metabolite studies revealed that amide hydrolysis in D-pocket was...
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) 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...
ABSTRACT Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract infections in infants, young children, and the elderly. We report herein discovery characterization novel RSV polymerase (RSVpol) non-nucleoside inhibitor (NNI) chemotype that binds to previously undescribed, highly conserved site palm domain L protein. Consistent with observed mode inhibition, cryogenic electron microscopy (cryo-EM) revealed be adjacent nucleotide binding site. Minireplicon assays...
Respiratory syncytial virus (RSV) is a negative sense single-stranded RNA and one of the main causes severe lower respiratory tract infections in infants young children. RSV replication/transcription capping are ensured by viral Large (L) protein. The L protein contains polymerase domain associated with polyribonucleotidyl transferase its N-terminus, methyltransferase (MTase) followed C-terminal (CTD) enriched basic amino acids at C-terminus. MTase-CTD Mononegavirales forms clamp to...
Abstract All herpesviruses encode a conserved DNA polymerase that is required for viral genome replication and serves as an important therapeutic target. Currently available herpesvirus therapies include nucleoside non-nucleoside inhibitors (NNI) target the DNA-bound state of block replication. Here we report ternary complex crystal structure Herpes Simplex Virus 1 bound to 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution. PNU active site, displacing template strand inducing...
The global spread of the SARS-CoV-2 virus has resulted in emergence lineages which impact effectiveness immunotherapies and vaccines that are based on early Wuhan isolate. All currently approved employ spike protein S, as it is target for neutralizing antibodies. Here we describe two isolates with unusually large deletions N-terminal domain (NTD) spike. Cryo-EM structural analysis shows result complete reshaping NTD supersite, an antigenically important region NTD. For both variants...
Prolylcarboxypeptidase (PrCP) is a lysosomal serine carboxypeptidase that cleaves variety of C-terminal amino acids adjacent to proline and has been implicated in diseases such as hypertension obesity. Here, the robust production, purification crystallization glycosylated human PrCP from stably transformed CHO cells described. Purified yielded crystals belonging space group R32, with unit-cell parameters = b 181.14, c 240.13 Å, diffracted better than 2.8 Å resolution.
Allosteric integrase inhibitors (ALLINIs) bind to the lens epithelial-derived growth factor (LEDGF) pocket on HIV-1 (IN) and possess potent antiviral effects. Rather than blocking proviral integration, ALLINIs trigger IN conformational changes that have catastrophic effects viral maturation, rendering virions assembled in presence of noninfectious. A high-throughput screen for compounds disrupt IN·LEDGF interaction was executed, extensive triage led identification a t-butylsulfonamide...
<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...
The bile salt export pump (BSEP) assay is widely used to evaluate the potential for drug-induced liver injury (DILI) early in drug discovery process. While traditional liquid chromatography-mass spectrometry (LC-MS)-based approaches have been utilized BSEP activity testing, they intrinsic limitations either throughput or requirement sample preparation and are difficult scale up order screen candidates. Here we demonstrate use of two different high-throughput MS methods based on solid-phase...
Abstract Vaccine components based on viral fusion proteins require high stability of the native prefusion conformation for optimal potency and manufacturability. In case influenza B virus hemagglutinin (HA), stem's relies efficient cleavage. this study, we identified six pH-sensitive regions distributed across entire ectodomain where protonated histidines assume either a repulsive or an attractive role. Substitutions in these areas enhanced protein's expression, quality, its trimeric state....
As many processes in the preclinical drug discovery process become highly parallel, need to also produce a large number of different proteins parallel has acute, such as for protein crystallization and activity screening. In turn, requisite DNA constructions these must now be done at rate that requires automated cloning procedures, each with an intrinsic low failure probability per sample. The high-throughput solutions presented here achieve production 192 expression plasmids success greater...