Chimia最新文献

Natural products are an essential source of medicines, accounting for a large proportion of approved drugs nowadays. However, the isolation of active natural products from complex extracts is challenging. To address this bottleneck, a drug discovery strategy was developed in our lab, that combines the screening of an in-house crude plant extract library of more than 2,500 samples with an HPLC-based activity profiling approach. This workflow is used routinely in our group and was successfully applied to numerous natural product drug discovery projects.

Fluorescence spectroscopy and microscopy in biomolecular environments are usually performed in aqueous solution and preferably using red-emitting dyes. However, water quenches their fluorescence. We explore in this contribution how host-guest interactions between red-emitting fluorophores and macrocycles such as cyclodextrins and cucurbiturils can prevent quenching by shielding the dyes from water, thereby enhancing their brightness. We successfully apply this strategy in super-resolution imaging.

The determination of the absolute configuration of molecules bearing different stereogenic elements represents a fundamental and indispensable task in the field of stereochemistry. Whereas X-ray crystallographic analysis has been established as a broadly utilized and reliable technique to achieve this goal, limitations remain arising from the demanding requirements for the size and diffraction quality of the analyzed crystals. As an emerging technique, 3D microcrystal electron diffraction (3D ED) has increasingly been recognized to complement single crystal X-ray diffraction (SC-XRD). Having encountered challenges in determining the absolute configuration for the products obtained during the development of atroposelective aromatic ring-opening metathesis (AArROM), we herein describe in detail, how 3D ED allowed an assignment, which proved unfeasible using the conventional approach with X-ray crystallography.

Covalent modification of lysine residues has gained significant attention due to its potential application in drug development and chemical biology. Lysine is an essential amino acid, abundant in proteins, and plays a critical role in many biological processes. In this study, we investigated aldehydes for imine-based chemistries and their reactivity profiles using a lysine-surrogate. By monitoring reactions of various aldehydes and salicylaldehydes over time, we determined dissociation constants (KD) for each warhead, reflecting the binding affinity towards the surrogate substrate. Strikingly, our data revealed remarkable differences in affinity depending on the substitution of the warheads. Additionally, we analyzed the kinetic profile of selected aldehydes and salicylaldehydes, which revealed significant disparity in their reaction kinetics. Aldehydes reacted quickly, reaching equilibrium rapidly, whereas salicylaldehydes exhibited considerably slower reaction times, in some cases requiring several hours to reach equilibrium. These differences emphasize how the nature of the warhead structure influences the kinetics of covalent binding to lysine residues. Overall, our study provides valuable insights into the application of reversible covalency to target lysines with reactive warheads that can further inspire development of innovative chemical modifications for drug discovery and chemical biology.

Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules that sequester the endogenous protein degradation machinery of cells to induce degradation of targeted proteins. By bringing a target protein and a ubiquitin E3 ligase into close proximity, ubiquitin monomers can be transferred onto surface lysines of the protein, which is subsequently degraded by the proteasome. The functions of RNA- and DNA-binding proteins have been especially hard to modulate with small molecules. However, oligonucleotides that bind RNA- or DNA-binding proteins can be turned into oligonucleotide-based PROTACs to direct ubiquitination and degradation of these proteins. Here we summarize the current state of the field of oligonucleotide-based PROTACs that target RNA- or DNA-binding proteins.

Monovalent degraders can enhance pre-existing surface complementarity between a target protein and a ligase to induce target degradation via the proteasome. For the most part, degraders have been discovered serendipitously and structure-activity relationship (SAR) studies have been limited, making it difficult to rationally design new compounds. Here we discuss how work on the SAR of cyclin K degraders demonstrates that a broad range of compounds can stabilise protein-protein interactions to induce degradation and how it lays the foundation for further monovalent degrader discovery.

Glycosylation is a profound influencer of glycoprotein function. Glycans have a critical impact on health and disease, yet the tools to study them have trailed behind proteins and nucleic acids. O-GalNAc glycosylation involves the addition of N-acetylgalactosamine (GalNAc) to protein substrates. Dysregulation of O-GalNAc glycosylation is implicated in many pathologies such as cancer. Studying O-GalNAc glycosylation is complicated by the lack of a consensus sequence for initiation and the complex interdependence between a large family of 20 GalNAc transferases (GalNAc-Ts) in human cells. These issues necessitate precise methods of interrogating enzyme function. Herein, we discuss our own advances into the generation of precision tools to study O-GalNAc glycosylation and other glycosylation types. We discuss the use of bump-and-hole engineering to illuminate the roles of individual GalNAc-Ts. Engineering biosynthetic pathways enables cell line-specific uptake of chemical, editable sugars in co-culture settings. We provide an insight into the state-of-the-art in this field.

Targeted protein degradation (TPD) has emerged as an innovative therapeutic strategy, offering advantage over traditional approaches rooted in small-molecule inhibitors. Among the various modalities in TPD, proteolysis targeting chimeras (PROTACs) and molecular glue degraders (MGDs) have arisen as leading modalities, distinguished by their ability to induce protein degradation via the ubiquitin-proteasome system (UPS). In recent years, extensive research has focused on developing degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300) - two homologous multidomain enzymes critical for enhancer-mediated transcription. This review explores the state of the art in CBP/EP300 degraders, underscoring the significant potential of these synthetic bifunctional compounds as innovative chemical tools and highly promising anticancer agents.