A5088980863- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Computational Drug Discovery Methods
- Endoplasmic Reticulum Stress and Disease
- Chemical Synthesis and Analysis
- Career Development and Diversity
- HIV/AIDS drug development and treatment
- Mentoring and Academic Development
- Diversity and Career in Medicine
- Alzheimer's disease research and treatments
- Click Chemistry and Applications
- Cancer Treatment and Pharmacology
- Cytokine Signaling Pathways and Interactions
- Heat shock proteins research
- RNA and protein synthesis mechanisms
- Epigenetics and DNA Methylation
- Cholinesterase and Neurodegenerative Diseases
- HIV Research and Treatment
- Protein Degradation and Inhibitors
- Cell Adhesion Molecules Research
- RNA modifications and cancer
- Synthesis and Biological Evaluation
- Peptidase Inhibition and Analysis
- Lung Cancer Treatments and Mutations
- Health and Medical Research Impacts
University of Pittsburgh
2015-2024
University of Pennsylvania
2010-2024
Friedreich's Ataxia Research Alliance
2019
Children's Hospital of Philadelphia
2019
Philadelphia University
2005-2013
SRI International
2012
Discovery Institute
2007-2010
Princeton University
2003-2009
California University of Pennsylvania
2007
University of California, Irvine
2007
AAA ATPase conformational high jinks The protein p97 is an adenosine triphosphatase (ATPase) that uses energy from ATP hydrolysis to regulate substrates involved in intracellular quality control. Its role this central process makes it a target for cancer chemotherapy. Banerjee et al. used cryo-electron microscopy determine high-resolution structures multiple states of dynamic macromolecular machine. They also determined the structure ADP-bound state bound inhibitor. give insight into...
The replacement of a carboxylic acid with surrogate structure, or (bio)-isostere, is classical strategy in medicinal chemistry. general underlying principle that by maintaining the features critical for biological activity, but appropriately modifying physicochemical properties, improved analogs may result. In this context, systematic assessment properties isosteres would be desirable to enable more informed decisions potential replacements used analog design. Herein we report...
The presenilin containing γ-secretase complex is responsible for the regulated intramembraneous proteolysis of amyloid precursor protein (APP), Notch receptor, and a multitude other substrates. γ-Secretase catalyzes final step in generation Aβ<sub>40</sub> Aβ<sub>42</sub> peptides from APP. Amyloid β-peptides (Aβ peptides) aggregate to form neurotoxic oligomers, senile plaques, congophilic angiopathy, some cardinal pathologies associated with Alzheimer9s disease. Although inhibition this...
Friedreich ataxia (FRDA) is a progressive neuro- and cardio-degenerative disorder characterized by ataxia, sensory loss, hypertrophic cardiomyopathy. In most cases, the caused GAA repeat expansions in first introns of both alleles <i>FXN</i> gene, resulting decreased expression encoded protein, frataxin. Frataxin localizes to mitochondrial matrix required for iron-sulfur-cluster biosynthesis. Decreased frataxin associated with dysfunction, iron accumulation, increased oxidative stress....
Metabolic stability plays an important role in the success of drug candidates. First-pass metabolism is one major causes poor oral bioavailability and short half-life. Traditionally, metabolic was evaluated at a later stage discovery required laborious manual manipulations. With advance high-throughput screening, combinatorial chemistry, early profiling drug-like properties, automated rapid assays are needed to meet increasing demand throughput, speed, reproducibility earlier stages...
A tetrahydroquinoline oxocarbazate (PubChem CID 23631927) was tested as an inhibitor of human cathepsin L (EC 3.4.22.15) and entry blocker severe acute respiratory syndrome (SARS) coronavirus Ebola pseudotype virus. In the inhibition assay, caused a time-dependent 17-fold drop in IC<sub>50</sub> from 6.9 nM (no preincubation) to 0.4 (4-h preincubation). Slowly reversible demonstrated dilution assay. transient kinetic analysis using single-step competitive model provided rate constants...
SAR on HTS hits 1 and 2 led to the potent, Notch-1-sparing GSI 9, which lowered brain Abeta in Tg2576 mice at 100 mg/kg po. Converting metabolically labile methyl groups 9 trifluoromethyl afforded more stable analogue 10, had improved vivo potency. Further side chain modification potent begacestat (5), was selected for development treatment of Alzheimer's disease.
Inclusions comprised of fibrils the microtubule- (MT-) associated protein tau are found in brains those with Alzheimer's disease (AD) and other neurodegenerative tauopathies. The pathology that is observed these diseases believed to result from formation toxic oligomers or and/or loss normal function due its sequestration into insoluble deposits. Hence, small molecules prevent oligomerization fibrillization might have therapeutic value. Indeed, examples such compounds been published, but...
West Nile virus (WNV), a member of the Flavividae family, is mosquito-borne, emerging pathogen. In addition to WNV, family includes dengue, yellow fever, and Japanese encephalitis viruses, which affect millions individuals worldwide. Because countermeasures are currently unavailable, flaviviral therapy urgently required. The two-component nonstructural NS2B-NS3 proteinase (protease [pro]) essential for viral life cycle and, consequently, promising drug target. We report here results...
Pharmacological inhibition of dietary lipid absorption induces favorable changes in serum lipoprotein levels patients that are at risk for cardiovascular disease and is considered an adjuvant or alternative treatment with HMG-CoA reductase inhibitors (statins). Here we demonstrate the feasibility identifying novel intestinal using zebrafish system. A pilot screen unbiased chemical library identified compounds inhibited processing fluorescent analogues live larvae. Secondary assays those...
Unique chemical methodology enables the synthesis of innovative and diverse scaffolds chemotypes allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes proteins and/or pathways whose functions are not fully understood. We describe identification, characterization, evolution two probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified compound, MARPIN (ATM ATR...
Exploratory SAR studies of a new phenyl indole chemotype for p97 inhibition revealed C-5 substituent effects in the ADPGlo assay that did not fully correlate with either electronic or steric factors. A focused series methoxy-, trifluoromethoxy-, methyl-, trifluoromethyl-, pentafluorosulfanyl-, and nitro-analogues was found to exhibit IC50s from low nanomolar double-digit micromolar. Surprisingly, we trifluoromethoxy-analogue biochemically better match trifluoromethyl-substituted lead...
Abstract Upregulation of endogenous utrophin offers great promise for treating DMD, as it can functionally compensate the lack dystrophin caused by DMD gene mutations, without immunogenic concerns associated with delivering dystrophin. However, post-transcriptional repression mechanisms targeting 5′ and 3′ untranslated regions (UTRs) mRNA significantly limit magnitude upregulation achievable promoter activation. Using a 5′3′UTR reporter assay, we performed high-throughput screen (HTS) small...
A series of isomeric 2',3'-dideoxynucleosides which contains a modified carbohydrate moiety has been prepared. This class compounds was designed to mimic the activity known anti-HIV dideoxynucleosides, while imparting enhanced chemical and enzymatic stability. Isonucleosides containing standard heterocyclic bases (A, C, G, T) were synthesized via nucleophilic addition base an sugar unit. Modified derivatives generated by manipulation intact isonucleoside. Two compound prepared, iso-ddA (1)...