A β-hydroxybutyrate shunt pathway generates anti-obesity ketone metabolites.

β-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids.

A secondary β-hydroxybutyrate metabolic pathway linked to energy balance.

β-hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve interconversion of BHB and primary energy intermediates. Here we show that CNDP2 controls a previously undescribed secondary BHB metabolic pathway via enzymatic conjugation of BHB and free amino acids.

Targeted protein relocalization via protein transport coupling.

Subcellular protein localization regulates protein function and can be corrupted in cancers and neurodegenerative diseases. The rewiring of localization to address disease-driving phenotypes would be an attractive targeted therapeutic approach. Molecules that harness the trafficking of a shuttle protein to control the subcellular localization of a target protein could enforce targeted protein relocalization and rewire the interactome.

Molecular glues and induced proximity: An evolution of tools and discovery.

Small molecule molecular glues can nucleate protein complexes and rewire interactomes. Molecular glues are widely used as probes for understanding functional proximity at a systems level, and the potential to instigate event-driven pharmacology has motivated their application as therapeutics. Despite advantages such as cell permeability and the potential for low off-target activity, glues are still rare when compared to canonical inhibitors in therapeutic development.

Elucidating the cellular determinants of targeted membrane protein degradation by lysosome-targeting chimeras.

Targeted protein degradation can provide advantages over inhibition approaches in the development of therapeutic strategies. Lysosome-targeting chimeras (LYTACs) harness receptors, such as the cation-independent mannose 6-phosphate receptor (CI-M6PR), to direct extracellular proteins to lysosomes. In this work, we used a genome-wide CRISPR knockout approach to identify modulators of LYTAC-mediated membrane protein degradation in human cells.

An exercise-inducible metabolite that suppresses feeding and obesity.

Exercise confers protection against obesity, type 2 diabetes and other cardiometabolic diseases. However, the molecular and cellular mechanisms that mediate the metabolic benefits of physical activity remain unclear. Here we show that exercise stimulates the production of N-lactoyl-phenylalanine (Lac-Phe), a blood-borne signalling metabolite that suppresses feeding and obesity.

Recent advances in induced proximity modalities.

Challenging disease targets necessitate new approaches for therapeutic intervention. Rewiring protein-biomolecule interactions with proximity-inducing agents extends intervention opportunities beyond target agonism or inhibition. Spanning varied molecular phenotypes and diverse target classes, proximity-inducing agents demonstrate immense potential across target degradation, cleavage, and post-translational editing.

Taming transcription factors with TRAFTACs.

Transcription factors play central roles in numerous diseases yet are notoriously challenging targets for drug development. In this issue of Cell Chemical Biology, Samarasinghe et al. (2021) describe a modular approach to targeting transcription factors for degradation with TRAFTACs, without the need for extensive ligand development campaigns.

Degradation from the outside in: Targeting extracellular and membrane proteins for degradation through the endolysosomal pathway.

Targeted protein degradation (TPD) is a promising strategy to remove deleterious proteins for therapeutic benefit and to probe biological pathways. The past two decades have witnessed a surge in the development of technologies that rely on intracellular machinery to degrade challenging cytosolic targets. However, these TPD platforms leave the majority of extracellular and membrane proteins untouched.

LYTACs that engage the asialoglycoprotein receptor for targeted protein degradation.

Selective protein degradation platforms have afforded new development opportunities for therapeutics and tools for biological inquiry. The first lysosome-targeting chimeras (LYTACs) targeted extracellular and membrane proteins for degradation by bridging a target protein to the cation-independent mannose-6-phosphate receptor (CI-M6PR). Here, we developed LYTACs that engage the asialoglycoprotein receptor (ASGPR), a liver-specific lysosome-targeting receptor, to degrade extracellular proteins in a cell-type-specific manner.

Spreading of a mycobacterial cell-surface lipid into host epithelial membranes promotes infectivity.

Several virulence lipids populate the outer cell wall of pathogenic mycobacteria. Phthiocerol dimycocerosate (PDIM), one of the most abundant outer membrane lipids, plays important roles in both defending against host antimicrobial programs and in evading these programs altogether. Immediately following infection, mycobacteria rely on PDIM to evade Myd88-dependent recruitment of microbicidal monocytes which can clear infection.

Lysosome-targeting chimaeras for degradation of extracellular proteins.

The majority of therapies that target individual proteins rely on specific activity-modulating interactions with the target protein-for example, enzyme inhibition or ligand blocking. However, several major classes of therapeutically relevant proteins have unknown or inaccessible activity profiles and so cannot be targeted by such strategies. Protein-degradation platforms such as proteolysis-targeting chimaeras (PROTACs) and others (for example, dTAGs, Trim-Away, chaperone-mediated autophagy targeting and SNIPERs) have been developed for proteins that are typically difficult to target; however, these methods involve the manipulation of intracellular protein degradation machinery and are therefore fundamentally limited to proteins that contain cytosolic domains to which ligands can bind and recruit the requisite cellular components.

Membrane-tethered mucin-like polypeptides sterically inhibit binding and slow fusion kinetics of influenza A virus.

The mechanism(s) by which cell-tethered mucins modulate infection by influenza A viruses (IAVs) remain an open question. Mucins form both a protective barrier that can block virus binding and recruit IAVs to bind cells via the sialic acids of cell-tethered mucins. To elucidate the molecular role of mucins in flu pathogenesis, we constructed a synthetic glycocalyx to investigate membrane-tethered mucins in the context of IAV binding and fusion.

Catalytic, Enantioselective 1,2-Difluorination of Cinnamamides.

The enantio- and diastereoselective synthesis of 1,2-difluorides via chiral aryl iodide-catalyzed difluorination of cinnamamides is reported. The method uses HF-pyridine as a fluoride source and mCPBA as a stoichiometric oxidant to turn over catalyst, and affords compounds containing vicinal, fluoride-bearing stereocenters. Selectivity for 1,2-difluorination versus a rearrangement pathway resulting in 1,1-difluorination is enforced through anchimeric assistance from a N- tert-butyl amide substituent.

Catalytic Diastereo- and Enantioselective Fluoroamination of Alkenes.

The stereoselective synthesis of syn-β-fluoroaziridine building blocks via chiral aryl iodide-catalyzed fluorination of allylic amines is reported. The method employs HF-pyridine as a nucleophilic fluoride source together with mCPBA as a stoichiometric oxidant, and affords access to arylethylamine derivatives featuring fluorine-containing stereocenters in high diastereo- and enantioselectivity. Catalyst-controlled diastereoselectivity in the fluorination of chiral allylic amines enabled the preparation of highly enantioenriched 1,3-difluoro-2-amines bearing three contiguous stereocenters.

Lewis acid enhancement by hydrogen-bond donors for asymmetric catalysis.

Small-molecule dual hydrogen-bond (H-bond) donors such as ureas, thioureas, squaramides, and guanidinium ions enjoy widespread use as effective catalysts for promoting a variety of enantioselective reactions. However, these catalysts are only weakly acidic and therefore require highly reactive electrophilic substrates to be effective. We introduce here a mode of catalytic activity with chiral H-bond donors that enables enantioselective reactions of relatively unreactive electrophiles.

Catalytic 1,3-Difunctionalization via Oxidative C-C Bond Activation.

Electronegative substituents arrayed in 1,3-relationships along saturated carbon frameworks can exert strong influence over molecular conformation due to dipole minimization effects. Simple and general methods for incorporation of such functional group relationships could thus provide a valuable tool for modulating molecular shape. Here, we describe a general strategy for the 1,3-oxidation of cyclopropanes using aryl iodine(I-III) catalysis, with emphasis on 1,3-difluorination reactions.

Enantioselective, Catalytic Fluorolactonization Reactions with a Nucleophilic Fluoride Source.

The enantioselective synthesis of 4-fluoroisochromanones via chiral aryl iodide-catalyzed fluorolactonization is reported. This methodology uses HF-pyridine as a nucleophilic fluoride source with a peracid stoichiometric oxidant and provides access to lactones containing fluorine-bearing stereogenic centers in high enantio- and diastereoselectivity. The regioselectivity observed in these lactonization reactions is complementary to that obtained with established asymmetric electrophilic fluorination protocols.

Catalytic, asymmetric difluorination of alkenes to generate difluoromethylated stereocenters.

Difluoromethyl groups possess specific steric and electronic properties that invite their use as chemically inert surrogates of alcohols, thiols, and other polar functional groups important in a wide assortment of molecular recognition processes. We report here a method for the catalytic, asymmetric, migratory geminal difluorination of β-substituted styrenes to access a variety of products bearing difluoromethylated tertiary or quaternary stereocenters. The reaction uses commercially available reagents (m-chloroperbenzoic acid and hydrogen fluoride pyridine) and a simple chiral aryl iodide catalyst and is carried out readily on a gram scale.

Catalytic, Diastereoselective 1,2-Difluorination of Alkenes.

We describe a direct, catalytic approach to the 1,2-difluorination of alkenes. The method utilizes a nucleophilic fluoride source and an oxidant in conjunction with an aryl iodide catalyst and is applicable to alkenes with all types of substitution patterns. In general, the vicinal difluoride products are produced with high diastereoselectivities.

Chemoselective Pd-catalyzed oxidation of polyols: synthetic scope and mechanistic studies.

The regio- and chemoselective oxidation of unprotected vicinal polyols with [(neocuproine)Pd(OAc)]2(OTf)2 (1) (neocuproine = 2,9-dimethyl-1,10-phenanthroline) occurs readily under mild reaction conditions to generate α-hydroxy ketones. The oxidation of vicinal diols is both faster and more selective than the oxidation of primary and secondary alcohols; vicinal 1,2-diols are oxidized selectively to hydroxy ketones, whereas primary alcohols are oxidized in preference to secondary alcohols. Oxidative lactonization of 1,5-diols yields cyclic lactones.

Adiabatic ring opening in tethered naphthalene and anthracene cycloadducts.

The cycloadducts of tethered naphthalene and anthracene derivatives undergo photochemical ring opening to an electronically excited product with adiabatic yields up to 90%.