ArticleJournal of the American Chemical Society2016
Ribosome-Templated Azide-Alkyne Cycloadditions: Synthesis of Potent Macrolide Antibiotics by In Situ Click Chemistry.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 64 citations in OpenAlex.
- Click Reactions in Kinetic Target-Guided Synthesis: Progress in the Discovery of Inhibitors for Biological Targets.Methods and protocols · 2026Review
- Synthesis and Evaluation of DNA Cross-linkers by Click Chemistry-Mediated Heterodimerization of Nor-Tomaymycins.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- New strategies to enhance the efficiency and precision of drug discovery.Frontiers in pharmacology · 2025Review
- Chemically Induced Dimerization via Nanobody Binding Facilitates in Situ Ligand Assembly and On-Demand GPCR Activation.JACS Au · 2024Article
- Shotgun Kinetic Target-Guided Synthesis Approach Enables the Discovery of Small-Molecule Inhibitors against Pathogenic Free-Living Amoeba Glucokinases.ACS infectious diseases · 2023Article
- Going beyond Binary: Rapid Identification of Protein-Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach.Journal of medicinal chemistry · 2023Article
- Sulfur fluoride exchange.Nature reviews. Methods primers · 2023Article
- Alternative approaches utilizing click chemistry to develop next-generation analogs of solithromycin.European journal of medicinal chemistry · 2022Article
- Synthesis, Biological Evaluation, and Computational Analysis of Biaryl Side-Chain Analogs of Solithromycin.ChemMedChem · 2021Article
- Kinetic Target-Guided Synthesis of Small-Molecule G-Quadruplex Stabilizers.ChemistryOpen · 2020Article
- Scaffold Modifications in Erythromycin Macrolide Antibiotics. A Chemical Minireview.Molecules (Basel, Switzerland) · 2020Review
- Article
- Self-triggered click reaction in an Alzheimer's disease model:Chemical science · 2019Article
- Fixing the Unfixable: The Art of Optimizing Natural Products for Human Medicine.Journal of medicinal chemistry · 2019Review
- Protein-Catalyzed Capture Agents.Chemical reviews · 2019Review
- Optimization and Evaluation of Site-Identification by Ligand Competitive Saturation (SILCS) as a Tool for Target-Based Ligand Optimization.Journal of chemical information and modeling · 2019Article
- Synthesis and biological evaluation of solithromycin analogs against multidrug resistant pathogens.Bioorganic & medicinal chemistry letters · 2019Article
- Ribosome-Templated Azide-Alkyne Cycloadditions Using Resistant Bacteria as Reaction Vessels:ACS medicinal chemistry letters · 2018Article
- Cell-Based Kinetic Target-Guided Synthesis of an Enzyme Inhibitor.ACS medicinal chemistry letters · 2018Article
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14 authors at 3 institutions in 1 country.
Funding
Abstract
Over half of all antibiotics target the bacterial ribosome-nature's complex, 2.5 MDa nanomachine responsible for decoding mRNA and synthesizing proteins. Macrolide antibiotics, exemplified by erythromycin, bind the 50S subunit with nM affinity and inhibit protein synthesis by blocking the passage of nascent oligopeptides. Solithromycin (1), a third-generation semisynthetic macrolide discovered by combinatorial copper-catalyzed click chemistry, was synthesized in situ by incubating either E. coli 70S ribosomes or 50S subunits with macrolide-functionalized azide 2 and 3-ethynylaniline (3) precursors. The ribosome-templated in situ click method was expanded from a binary reaction (i.e., one azide and one alkyne) to a six-component reaction (i.e., azide 2 and five alkynes) and ultimately to a 16-component reaction (i.e., azide 2 and 15 alkynes). The extent of triazole formation correlated with ribosome affinity for the anti (1,4)-regioisomers as revealed by measured Kd values. Computational analysis using the site-identification by ligand competitive saturation (SILCS) approach indicated that the relative affinity of the ligands was associated with the alteration of macrolactone+desosamine-ribosome interactions caused by the different alkynes. Protein synthesis inhibition experiments confirmed the mechanism of action. Evaluation of the minimal inhibitory concentrations (MIC) quantified the potency of the in situ click products and demonstrated the efficacy of this method in the triaging and prioritization of potent antibiotics that target the bacterial ribosome. Cell viability assays in human fibroblasts confirmed 2 and four analogues with therapeutic indices for bactericidal activity over in vitro mammalian cytotoxicity as essentially identical to solithromycin (1).
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