Friday, November 27, 2020

Targeted Covalent Inhibitors for the Treatment of Malaria?

Shashank Kulkarni, Klaus Urbahns, and Thomas Spangenberg
ACS Infectious Diseases 2020 6 (11), 2815-2817
DOI: 10.1021/acsinfecdis.0c00684

Malaria is a vector-borne disease caused by protozoan parasites of the genus Plasmodium. According to the World Health Organization, it is one of the most serious infectious diseases threatening more than 3 billion people worldwide. In recent years, targeted covalent inhibitors (TCIs) have gained a lot of attention and several TCI-based drugs have been approved across different therapeutic areas. For malaria, surprisingly, this approach has not been explored in depth even though lot of advancements have been made in understanding the biology of the parasite. Herein, we present our views on exploring TCIs as a new class of antimalarial agents.

Sunday, November 8, 2020

Development and Application of a Chemical Probe Based on a Neuroprotective Flavonoid Hybrid for Target Identification Using Activity-Based Protein Profiling

Sandra Gunesch, David Soriano-Castell, Stephanie Lamer, Andreas Schlosser, Pamela Maher, and Michael Decker

ACS Chemical Neuroscience 2020

DOI: 10.1021/acschemneuro.0c00589

Alzheimer’s disease (AD) is the most common form of dementia, and up to now, there are no disease-modifying drugs available. Natural product hybrids based on the flavonoid taxifolin and phenolic acids have shown a promising pleiotropic neuroprotective profile in cell culture assays and even disease-modifying effects in vivo. However, the detailed mechanisms of action remain unclear. To elucidate the distinct intracellular targets of 7-O-esters of taxifolin, we present in this work the development and application of a chemical probe, 7-O-cinnamoyltaxifolin-alkyne, for target identification using activity-based protein profiling. 7-O-Cinnamoyltaxifolin-alkyne remained neuroprotective in all cell culture assays. Western blot analysis showed a comparable influence on the same intracellular pathways as that of the lead compound 7-O-cinnamoyltaxifolin, thereby confirming its suitability as a probe for target identification experiments. Affinity pulldown and MS analysis revealed adenine nucleotide translocase 1 (ANT-1) and sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) as intracellular interaction partners of 7-O-cinnamoyltaxifolin-alkyne and thus of 7-O-esters of taxifolin.

An Untargeted Approach for Revealing Electrophilic Metabolites

Yan Yu, Henry H. Le, Brian J. Curtis, Chester J. J. Wrobel, Bingsen Zhang, Danielle N. Maxwell, Judy Y. Pan, and Frank C. Schroeder

ACS Chemical Biology 2020

DOI: 10.1021/acschembio.0c00706

Reactive electrophilic intermediates such as coenzyme A esters play central roles in metabolism but are difficult to detect with conventional strategies. Here, we introduce hydroxylamine-based stable isotope labeling to convert reactive electrophilic intermediates into stable derivatives that are easily detectable via LC–MS. In the model system Caenorhabditis elegans, parallel treatment with 14NH2OH and 15NH2OH revealed >1000 labeled metabolites, e.g., derived from peptide, fatty acid, and ascaroside pheromone biosyntheses. Results from NH2OH treatment of a pheromone biosynthesis mutant, acox-1.1, suggested upregulation of thioesterase activity, which was confirmed by gene expression analysis. The upregulated thioesterase contributes to the biosynthesis of a specific subset of ascarosides, determining the balance of dispersal and attractive signals. These results demonstrate the utility of NH2OH labeling for investigating complex biosynthetic networks. Initial results with Aspergillus and human cell lines indicate applicability toward uncovering reactive metabolomes in diverse living systems.

Saturday, November 7, 2020

Complex Crystal Structures of EGFR with Third-Generation Kinase Inhibitors and Simultaneously Bound Allosteric Ligands

ACS Med. Chem. Lett. 2020


Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) and currently the gold-standard for the treatment of patients suffering from non-small cell lung cancer (NSCLC) harboring T790M-mutated epidermal growth factor receptor (EGFR). The outcome of the treatment, however, is limited by the emergence of the C797S resistance mutation. Allosteric inhibitors have a different mode of action and were developed to overcome this limitation. However, most of these innovative molecules are not effective as a single agent. Recently, mutated EGFR was successfully addressed with osimertinib combined with the allosteric inhibitor JBJ-04-125-02, but surprisingly, structural insights into their binding mode were lacking. Here, we present the first complex crystal structures of mutant EGFR in complex with third-generation inhibitors such as osimertinib and mavelertinib in the presence of simultaneously bound allosteric inhibitors. These structures highlight the possibility of further combinations targeting EGFR and lay the foundation for hybrid inhibitors as next-generation TKIs.

Sunday, November 1, 2020

Chemical Control of Quorum Sensing in E. coli: Identification of Small Molecule Modulators of SdiA and Mechanistic Characterization of a Covalent Inhibitor

Matthew J. Styles, Stephen A. Early, Trisha Tucholski, Korbin H. J. West, Ying Ge, and Helen E. Blackwell

ACS Infectious Diseases 2020

DOI: 10.1021/acsinfecdis.0c00654

Enterohemorrhagic Escherichia coli (EHEC) is the causative agent of severe diarrheal disease in humans. Cattle are the natural reservoir of EHEC, and approximately 75% of EHEC infections in humans stem from bovine products. Many common bacterial pathogens, including EHEC, rely on chemical communication systems, such as quorum sensing (QS), to regulate virulence and facilitate host colonization. EHEC uses SdiA from E. coli (SdiAEC), an orphan LuxR-type receptor, to sense N-acyl l-homoserine lactone (AHL) QS signals produced by other members of the bovine enteric microbiome. SdiAEC regulates two phenotypes critical for colonizing cattle: acid resistance and the formation of attaching and effacing lesions. Despite the importance of SdiAEC, there is very little known about its selectivity for different AHL signals, and no chemical inhibitors that act specifically on SdiAEC have been reported. Such compounds would represent valuable tools to study the roles of QS in EHEC virulence. To identify chemical modulators of SdiAEC and delineate the structure–activity relationships (SARs) for AHL activity in this receptor, we report herein the screening of a focused library composed largely of AHLs and AHL analogues in an SdiAEC reporter assay. We describe the identity and SARs of potent modulators of SdiAEC activity, examine the promiscuity of SdiAEC, characterize the mechanism of a covalent inhibitor, and provide phenotypic assay data to support that these compounds can control SdiAEC-dependent acid resistance in E. coli. These SdiAEC modulators could be used to advance the study of LuxR-type receptor/ligand interactions, the biological roles of orphan LuxR-type receptors, and potential QS-based therapeutic approaches.

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...