ArticleBioorganic chemistry2026
Solvatochromic diacylglycerol-mimetic probes reveal distinct trafficking of DAG-like lipids to lipid droplets.
Article in Bioorganic chemistry, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Diacylglycerols (DAGs) are central intermediates in lipid metabolism and signaling, yet their trafficking within cellular membranes and lipid droplets remains difficult to visualize because DAGs are rapidly metabolized and chemically unstable as imaging probes. Here we report the design and characterization of a family of solvatochromic fluorescent lipid mimetics, termed DONDI, developed to mimic DAG while reporting on local membrane environments. These probes are based on a 1,8-naphthalimide fluorophore conjugated to modified aminoglycerol lipid backbones bearing oleoyl chains that mimic native glycerolipids. Biophysical characterization together with atomistic molecular dynamics simulations reveal probe-dependent membrane partitioning and hydrogen-bonding interactions that govern lipid-mimetic behavior and solvatochromic responses. Live-cell imaging demonstrates efficient cellular uptake and selective accumulation of DONDI probes within lipid droplets. Structure-function analysis identifies DONDI-5 as the closest structural and biophysical mimic of 1,2-diacylglycerol, characterized by rapid membrane uptake, strong lipid droplet enrichment, and prolonged intracellular retention without detectable redistribution to other cellular membranes. These properties enable sustained visualization of DAG-like lipid pools and reveal trafficking of DAG-like species to lipid droplets without prior conversion to triacylglycerols. Collectively, this work establishes a bioorganic strategy for constructing solvatochromic DAG-mimetic lipid probes and provides experimental insight into the distinct intracellular behavior of DAG relative to triacylglycerols.
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