Programming inactive RNA-binding small molecules into bioactive degraders.

Target occupancy is often insufficient to elicit biological activity, particularly for RNA, compounded by the longstanding challenges surrounding the molecular recognition of RNA structures by small molecules. Here we studied molecular recognition patterns between a natural-product-inspired small-molecule collection and three-dimensionally folded RNA structures. Mapping these interaction landscapes across the human transcriptome defined structure-activity relationships. Although RNA-binding compounds that bind to functional sites were expected to elicit a biological response, most identified interactions were predicted to be biologically inert as they bind elsewhere. We reasoned that, for such cases, an alternative strategy to modulate RNA biology is to cleave the target through a ribonuclease-targeting chimera, where an RNA-binding molecule is appended to a heterocycle that binds to and locally activates RNase L1. Overlay of the substrate specificity for RNase L with the binding landscape of small molecules revealed many favourable candidate binders that might be bioactive when converted into degraders. We provide a proof of concept, designing selective degraders for the precursor to the disease-associated microRNA-155 (pre-miR-155), JUN mRNA and MYC mRNA. Thus, small-molecule RNA-targeted degradation can be leveraged to convert strong, yet inactive, binding interactions into potent and specific modulators of RNA function.

Radical Carbonyl Umpolung Arylation via Dual Nickel Catalysis.

The formation of carbon-carbon bonds lies at the heart of synthetic organic chemistry and is widely applied to construct complex drugs, polymers, and materials. Despite its importance, catalytic carbonyl arylation remains comparatively underdeveloped, due to limited scope and functional group tolerance. Herein we disclose an umpolung strategy to achieve radical carbonyl arylation via dual catalysis. This redox-neutral approach provides a complementary method to construct Grignard-type products from (hetero)aryl bromides and aliphatic aldehydes, without the need for pre-functionalization. A sequential activation, hydrogen-atom transfer, and halogen atom transfer process could directly convert aldehydes to the corresponding ketyl-type radicals, which further react with aryl-nickel intermediates in an overall polarity-reversal process. This radical strategy tolerates─among others─acidic functional groups, heteroaryl motifs, and sterically hindered substrates and has been applied in the late-stage modification of drugs and natural products.

Bipolar Imidazolium-Based Lipid Analogues for Artificial Archaeosomes.

Archaeal lipids have harvested biomedical and biotechnological interest because of their ability to form membranes with low permeability and enhanced temperature and pressure stability. Because of problems in isolating archaeal lipids, chemical synthesis appears to be a suitable means of producing model lipids that mimic the biological counterparts. Here, we introduce a new concept: we synthesized bipolar alkylated imidazolium salts of different chain lengths (BIm10-32) and studied their structure and lyotropic phase behavior. Furthermore, mixtures of the bolalipid analogues with phospholipid model biomembranes of diverse complexity were studied. DSC, fluorescence and FTIR spectroscopy, confocal fluorescence microscopy, DLS, SAXS, and TEM were used to reveal changes in lipid phase behavior, fluidity, the lipid's conformational order, and membrane morphology over a wide range of temperatures and for selected pressures. It could be shown that the long-chain BImN32 can form monolayer sheets. Integrated in phospholipid membranes, it reveals a fluidizing effect. Here, the two polar head groups, connected by a long alkyl chain, enable the integration into the bilayer. Interestingly, addition of BImN32 to fluid DPPC liposomes increased the lipid packing markedly, rendering the membrane system more stable at higher temperatures. The membrane system is also stable against compression as indicated by the high-pressure stability of the system, mimicking an archaeal lipid-like behavior. BImN32 incorporation into raft-like anionic model biomembranes led to marked changes in lateral membrane organization, topology, and fusogenicity of the membrane. Overall, it was found that long-chain imidazolium-based bolalipid analogues can help adjust membrane's biophysical properties, while the imidazolium headgroup provides the ability for crucial electrostatic interaction for vesicle fusion or selective interaction with membrane-related signaling molecules and polypeptides in a synthetically tractable manner. The results obtained may help to develop new approaches for rational design of extremophilic bolalipid-based liposomes for various applications, including delivery of drugs and vaccines.

Interaction of imidazolium-based lipids with phospholipid bilayer membranes of different complexity.

In recent years, alkylated imidazolium salts have been shown to affect lipid membranes and exhibit general cytotoxicity as well as significant anti-tumor activity. Here, we examined the interactions of a sterically demanding, biophysically unexplored imidazolium salt, 1,3-bis(2,6-diisopropylphenyl)-4,5-diundecylimidazolium bromide (C11IPr), on the physico-chemical properties of various model biomembrane systems. The results are compared with those for the smaller headgroup variant 1,3-dimethyl-4,5-diundecylimidazolium iodide (C11IMe). We studied the influence of these two lipid-based imidazolium salts at concentrations from 1 to about 10 mol% on model biomembrane systems of different complexity, including anionic heterogeneous raft membranes which are closer to natural membranes. Fluorescence spectroscopic, DSC, surface potential and FTIR measurements were carried out to reveal changes in membrane thermotropic phase behavior, lipid conformational order, fluidity and headgroup charge. Complementary AFM and confocal fluorescence microscopy measurements allowed us to detect changes in the lateral organization and membrane morphology. Both lipidated imidazolium salts increase the membrane fluidity and lead to a deterioration of the lateral domain structure of the membrane, in particular for C11IPr owing to its bulkier headgroup. Moreover, partitioning of the lipidated imidazolium salts into the lipid vesicles leads to marked changes in lateral organization, curvature and morphology of the lipid vesicles at high concentrations, with C11IPr having a more pronounced effect than C11IMe. Hence, these compounds seem to be vastly suitable for biochemical and biotechnological engineering, with high potentials for antimicrobial activity, drug delivery and gene transfer.