Efrat Resnick
A5075876453- Enzyme Structure and Function
- Nanoplatforms for cancer theranostics
- X-ray Diffraction in Crystallography
- Computational Drug Discovery Methods
- S100 Proteins and Annexins
- Chemical Thermodynamics and Molecular Structure
- Nanoparticle-Based Drug Delivery
- Boron Compounds in Chemistry
- Click Chemistry and Applications
- Radioactive element chemistry and processing
- Spectroscopy Techniques in Biomedical and Chemical Research
- Peptidase Inhibition and Analysis
- Cancer Research and Treatments
- SARS-CoV-2 and COVID-19 Research
- Trace Elements in Health
- Crystallization and Solubility Studies
- Protein purification and stability
- Synthesis and biological activity
- Protein Degradation and Inhibitors
- Mass Spectrometry Techniques and Applications
- Ubiquitin and proteasome pathways
- RNA and protein synthesis mechanisms
- Endoplasmic Reticulum Stress and Disease
- thermodynamics and calorimetric analyses
- Redox biology and oxidative stress
Weizmann Institute of Science
2018-2023
Minneapolis VA Medical Center
2006
University of Iowa
2006
University of California, Los Angeles
2006
Alzheimer’s Disease Neuroimaging Initiative
2006
Geriatric Research Education and Clinical Center
2006
University of Southern California
2006
Medical University of South Carolina
2006
Office of Extramural Research
2006
Temple University
1986
Abstract COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through combined mass spectrometry X-ray approach SARS-CoV-2 main protease, one two cysteine viral proteases essential replication. Our...
Covalent probes can display unmatched potency, selectivity, and duration of action; however, their discovery is challenging. In principle, fragments that irreversibly bind target overcome the low affinity limits reversible fragment screening, but such electrophilic were considered nonselective rarely screened. We hypothesized mild electrophiles might selectivity challenge constructed a library 993 mildly fragments. characterized this by new high-throughput thiol-reactivity assay screened...
Targeted covalent inhibitors are an important class of drugs and chemical probes. However, relatively few electrophiles meet the criteria for successful inhibitor design. Here we describe α-substituted methacrylamides as a new suitable targeted inhibitors. While typically α-substitutions inactivate acrylamides, show that hetero have higher thiol reactivity undergo conjugated addition–elimination reaction ultimately releasing substituent. Their toward thiols is tunable correlates with pKa/pKb...
Chemical modifications of native proteins can affect their stability, activity, interactions, localization, and more. However, there are few nongenetic methods for the installation chemical at a specific protein site in cells. Here we report covalent ligand directed release (CoLDR) site-specific labeling strategy, which enables variety functional tags on target while releasing directing ligand. Using this approach, were able to label various such as BTK, K-RasG12C, SARS-CoV-2 PLpro with...
Summary COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through combined mass spectrometry X-ray approach SARS-CoV-2 main protease, one two cysteine viral proteases essential replication. Our...
A common challenge in drug design pertains to finding chemical modifications a ligand that increases its affinity the target protein. An underutilized advance is increase structural biology throughput, which has progressed from an artisanal endeavor monthly throughput of hundreds different ligands against protein modern synchrotrons. However, missing piece framework turns high-throughput crystallography data into predictive models for design. Here, we designed simple machine learning...
Abstract Covalent probes can display unmatched potency, selectivity and duration of action, however, their discovery is challenging. In principle, fragments that irreversibly bind target overcome the low affinity limits reversible fragment screening. Such electrophilic were considered non-selective rarely screened. We hypothesized mild electrophiles might challenge, constructed a library 993 mildly fragments. characterized this by new high-throughput thiol-reactivity assay screened them...
High-throughput nanomole-scale synthesis allows for late-stage functionalization (LSF) of compounds in an efficient and economical manner. Here, we demonstrated that copper-catalyzed azide-alkyne cycloaddition could be used the LSF covalent kinase inhibitors at nanoscale, enabling hundreds did not require purification biological assay screening, thus reducing experimental time drastically. We generated crude libraries MKK7, derived from two different parental precursors, analyzed them via...
Abstract The thioredoxin superfamily has expanded and diverged extensively throughout evolution such that distant members no longer show appreciable sequence homology. Nevertheless, redox‐active thioredoxin‐fold proteins functioning in diverse physiological contexts often share canonical amino acids near the active‐site (di‐)cysteine motif. Quiescin sulfhydryl oxidase 1 (QSOX1), a catalyst of disulfide bond formation secreted by fibroblasts, is multi‐domain enzyme with certain similarities...
Abstract Designing covalent inhibitors is a task of increasing importance in drug discovery. Efficiently designing irreversible inhibitors, though, remains challenging. Here, we present covalentizer , computational pipeline for creating based on complex structures targets with known reversible binders. For each ligand, create custom-made focused library analogs. We use docking, to dock these tailored libraries and find those that can bind covalently nearby cysteine while keeping some the...
Abstract The peptidyl-prolyl cis-trans isomerase, Pin1, acts as a unified signaling hub that is exploited in cancer to activate oncogenes and inactivate tumor suppressors, particular through up-regulation of c-Myc target genes. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened electrophilic fragment library discover covalent inhibitors targeting Pin1’s active site nucleophile - Cys113, leading the development Sulfopin, double-digit nanomolar...
Aims: The post-translational oxidation of methionine to sulfoxide (MetSO) is a reversible process, enabling the repair oxidative damage proteins and use sulfoxidation as regulatory switch. MetSO reductases catalyze stereospecific reduction MetSO. One mammalian reductases, MsrB3, has signal sequence for entry into endoplasmic reticulum (ER). In ER, MsrB3 expected encounter distinct redox environment compared with its paralogs in cytosol, nucleus, mitochondria. We sought determine location...
Outbreaks of human epidemic nonbacterial gastroenteritis are mainly caused by noroviruses. Viral replication requires a 3C-like cysteine protease (3CLpro) which processes the 200 kDa viral polyprotein into six functional proteins. The 3CLpro has attracted much interest due to its potential as target for antiviral drugs. A system growing high-quality crystals native Southampton norovirus (SV3CP) been established, allowing ligand-free crystal structure be determined 1.3 Å in tetrameric state....