In This Issue Cite This: ACS Med. Chem. Lett. 2018, 9, 860−860
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DECIPHERING BINDING INTERACTIONS OF IL-23R WITH HDX-MS: MAPPING PROTEIN AND MACROCYCLIC DODECAPEPTIDE LIGANDS Interleukin-23 (IL-23) is a heterodimeric cytokine, which is implicated in inflammation, autoimmune inflammatory disorders, and cancer. IL-23 binds to a receptor complex composed of IL-12Rβ1 and IL-23R; characterization of their interactions could facilitate discovery of therapeutics. In this issue, Sayago et al. (DOI: 10.1021/acsmedchemlett.8b00255) study the binding interaction between IL-23 and a peptide macrocycle with IL-23R, using computational analyses and hydrogen/deuterium exchange coupled to mass spectrometry (HDX-MS). HDX-MS is a biophysical characterization technique that can unveil solvent-exposed regions of a protein in deuterium solvent via rapid amide hydrogen to deuterium exchange in solvent-exposed regions. The study revealed the binding epitope of IL-23R:IL-23 in a solvent environment and uncovered, for the first time, the IL-23R binding site of a macrocyclic small molecule. These results may pave the way for development of small molecules targeting this complex for the treatment of autoimmune diseases as a less costly alternative to monoclonal antibodies.
showing >10,000 selectivity for activating PPARδ compared to PPARα and PPARγ and other nuclear receptors as well as favorable physicochemical properties and toxicity profile. In vitro and in vivo testing of this potent and selective PPARδ modulator showed elevated PPARδ target gene transcription in skeletal muscle, increased three PPARδ target genes, and improved fatty acid oxidation, supporting preclinical development of this candidate for DMD.
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RIBOSOME-TEMPLATED AZIDE−ALKYNE CYCLOADDITIONS USING RESISTANT BACTERIA AS REACTION VESSELS: IN CELLULO CLICK CHEMISTRY In situ click chemistry involves selectively combining reactive molecules via a biological target in an irreversible reaction. For example, in drug discovery, using in situ click chemistry one may assemble protein inhibitors from complementary building block reagents by utilizing the protein binding site to direct the in situ formation of functional products. In this issue, Jin et al. (DOI: 10.1021/acsmedchemlett.8b00248) demonstrate how this idea can be extended to an in cellulo click chemistry concept to create novel antibiotics. The authors employed antibiotic-resistant bacterial cells and show that the bacterial ribosome can template triazole formation. Proof-of-concept studies with the resistant Grampositive bacterium Staphylococcus aureus strain UCN18 demonstrated in cellulo synthesis of the antibiotic solithromycin. Additional studies with a library of alkyne fragments and the traditional MIC assay revealed that potent compounds were produced in greater amounts. This methodology does not require isolation of bacterial ribosomes or prior knowledge of mode-of-action and may be applicable to different bacterial strains, thus representing a promising strategy for the discovery of novel, narrow-spectrum antibiotics.
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SELECTIVE PPARδ MODULATORS IMPROVE MITOCHONDRIAL FUNCTION: POTENTIAL TREATMENT FOR DUCHENNE MUSCULAR DYSTROPHY (DMD) Duchenne Muscular Dystrophy (DMD) is a genetic neuromuscular disorder that leads to progressive muscle degeneration due to the absence of the protein dystrophin. Mitochondrial dysfunction contributes to abnormalities in muscle of DMD patients. The peroxisome proliferatoractivated receptor delta (PPARδ) has been shown to regulate mitochondrial functions in skeletal muscle and has been validated as a target for treating DMD. In the present issue, Lagu et al. (DOI: 10.1021/ acsmedchemlett.8b00287) report the optimization of a selective PPARδ modulator bearing a cis-amide with isosteric replacement of the cis-amide with five-membered heterocycles. Using available and new crystallographic data, the optimization resulted in an imidazole compound of subnanomolar potency © 2018 American Chemical Society
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Published: September 13, 2018 860
DOI: 10.1021/acsmedchemlett.8b00399 ACS Med. Chem. Lett. 2018, 9, 860−860
