A5076090619- SARS-CoV-2 and COVID-19 Research
- Computational Drug Discovery Methods
- Cytokine Signaling Pathways and Interactions
- Quinazolinone synthesis and applications
- interferon and immune responses
- Pharmacogenetics and Drug Metabolism
- Glutathione Transferases and Polymorphisms
- Protein Tyrosine Phosphatases
- Drug Transport and Resistance Mechanisms
- Chemical Synthesis and Analysis
- CRISPR and Genetic Engineering
- Synthesis and Biological Evaluation
- Signaling Pathways in Disease
- Tuberculosis Research and Epidemiology
- Protein Structure and Dynamics
- Animal Virus Infections Studies
- Biochemical and Molecular Research
- COVID-19 Clinical Research Studies
- Viral Infections and Immunology Research
- RNA and protein synthesis mechanisms
- Nuclear Receptors and Signaling
Takeda (United States)
2022-2024
St. Jude Children's Research Hospital
2024
University of Washington
2024
Takeda (Japan)
2023
Inhibition of the protein kinase CSNK2 with any 30 specific and selective inhibitors representing different chemotypes, blocked replication pathogenic human, bat, murine β-coronaviruses. The potency in-cell CSNK2A target engagement across set correlated antiviral activity genetic knockdown confirmed essential role holoenzyme in β-coronavirus replication. Spike endocytosis was by inhibition, indicating that due part to a suppression viral entry. inhibition may be viable for development...
3-Cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines, including the chemical probe SGC-CK2-1, are potent and selective inhibitors of CSNK2A in cells but have limited utility animal models due to their poor pharmacokinetic properties. While developing analogues with reduced intrinsic clearance potential for sustained exposure mice, we discovered that phase II conjugation by GST enzymes was a major metabolic transformation hepatocytes. A protocol codosing ethacrynic acid, covalent reversible...
A collaborative, open-science team undertook discovery of novel small molecule inhibitors the SARS-CoV-2 nsp16-nsp10 2′-O-methyltransferase using a high throughput screening approach with potential to reveal new inhibition strategies. This screen yielded compound 5a, ligand possessing an electron-deficient double bond, as inhibitor nsp16 activity. Surprisingly, X-ray crystal structures revealed that 5a covalently binds within previously unrecognized cryptic pocket near S-adenosylmethionine...
The pyrazolo[1,5-a]pyrimidine scaffold is a promising to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of 1,2,4-triazole group substitute key amide for binding present in many inhibitors. Crystallographic evidence demonstrates that replaces forming hydrogen bonds Lys68 water molecule buried ATP-binding pocket. This isosteric replacement improves potency metabolic stability at cost solubility. Optimization...
Small-molecule antivirals that prevent the replication of SARS-CoV-2 virus by blocking enzymatic activity its main protease (Mpro) are and will be a tenet pandemic preparedness. However, peptidic nature such compounds often precludes design within favorable physical property ranges, limiting cellular activity. Here we describe discovery peptide aldehyde Mpro inhibitors with potent antiviral This structure-activity relationship (SAR) exploration was guided use calculated hydration site...
3-cyano-7-cyclopropylamino-pyrazolo[1,5-a]pyrimidines, including the chemical probe SGC-CK2-1, are potent and selective inhibitors of CSNK2A in cells but have limited utility animal models due to their poor pharmacokinetic properties. While developing analogs with reduced intrinsic clearance potential for sustained exposure mice, we discovered that Phase II conjugation by GST enzymes was a major metabolic transformation hepatocytes. A protocol co-dosing ethacrynic acid, covalent reversible...
The host kinase casein 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug in vivo, potent and selective inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-
Inhibition of the protein kinase CSNK2 with any 30 specific and selective inhibitors representing different chemotypes, blocked replication pathogenic human murine β-coronaviruses. The potency in-cell CSNK2A target engagement across set correlated antiviral activity genetic knockdown confirmed essential role holoenzyme in β-coronavirus replication. Spike uptake was by inhibition, indicating that due part to a suppression viral entry. inhibition may be viable for development new broad...
Abstract Microtubule-associated protein tau is an intrinsically disordered (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which Alzheimer’s disease (AD). Despite keen interest disrupting or inhibiting aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This due, part, fact other IDPs do not exhibit a single well-defined conformation but instead populate fluctuating conformational ensemble...
The pyrazolo[1,5-a]pyrimidine scaffold is a promising to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of 1,2,4-triazole group substitute key amide for binding present in many inhibitors. Crystallographic evidence demonstrates that replaces forming hydrogen bonds Lys68 water molecule buried ATP-binding pocket. This isosteric replacement improves potency metabolic stability at cost solubility. Optimization...
The host kinase casein 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug in vivo, potent and selective inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5-a]pyrimidine scaffold possess outstanding potency selectivity for CSNK2, but bioavailability metabolic stability were often challenging. By strategically installing fluorine atom electron-rich phenyl ring of...
Microtubule-associated protein tau is an intrinsically disordered (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which Alzheimer’s disease (AD). Despite keen interest disrupting or inhibiting aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This due, part, fact other IDPs do not exhibit a single well-defined conformation but instead populate fluctuating conformational ensemble precludes...
Microtubule-associated protein tau is an intrinsically disordered (IDP) that forms characteristic fibrillar aggregates in several diseases, the most well-known of which Alzheimer’s disease (AD). Despite keen interest disrupting or inhibiting aggregation to treat AD and related dementias, there are currently no FDA-approved tau-targeting drugs. This due, part, fact other IDPs do not exhibit a single well-defined conformation but instead populate fluctuating conformational ensemble precludes...