The
majority of bioactive molecules act on membrane proteins or
intracellular targets and therefore needs to partition into or cross
biological membranes. Natural products often exhibit lipid modifications
to facilitate critical molecule–membrane interactions, and
in many cases their bioactivity is markedly reduced upon removal of
a lipid group. However, despite its importance in nature, lipid-conjugation
of small molecules is not commonly used in chemical biology and medicinal
chemistry, and the effect of such conjugation has not been systematically
studied. To understand the composition of lipids found in natural
products, we carried out a chemoinformatic characterization of the
“natural product lipidome”. According to this analysis,
lipidated natural products predominantly contain saturated medium-chain
lipids (MCLs), which are significantly shorter than the long-chain
lipids (LCLs) found in membranes and lipidated proteins. To study
the usefulness of such modifications in probe design, we systematically
explored the effect of lipid conjugation on five different small molecule
chemotypes and find that permeability, cellular retention, subcellular
localization, and bioactivity can be significantly modulated depending
on the type of lipid tail used. We demonstrate that MCL conjugation
can render molecules cell-permeable and modulate their bioactivity.
With all explored chemotypes, MCL-conjugates consistently exhibited
superior uptake or bioactivity compared to LCL-conjugates and either
comparable or superior uptake or bioactivity to short-chain lipid
(SCL)-conjugates. Together, our findings suggest that conjugation
of small molecules with MCLs could be a powerful strategy for the
design of probes and drugs.
Photopharmacology aims at the optical control of protein activity using synthetic photoswitches. This approach has been recently expanded to nuclear hormone receptors with the introduction of "photohormones" for the retinoic acid receptor, farnesoid X receptor, and estrogen receptor. Herein, we report the development and profiling of photoswitchable agonists for peroxisome proliferator-activated receptor γ (PPARγ). Based on known PPARγ ligands (MDG548, GW1929, and rosiglitazone), we have designed and synthesized azobenzene derivatives, termed AzoGW1929 and AzoRosi, which were confirmed to be active in cell-based assays. Subsequent computer-aided optimization of AzoRosi resulted in the photohormone AzoRosi-4, which bound and activated PPARγ preferentially in its lightactivated cis-configuration.
We report short ceramide analogs that can be activated with light and further functionalized using azide−alkyne click chemistry. These molecules, termed scaCers, exhibit increased cell permeability compared to their long-chain analogs as demonstrated using mass spectrometry and imaging. Notably, scaCers enable optical control of apoptosis, which is not observed with long-chain variants. Additionally, they function as photoswitchable substrates for sphingomyelin synthase 2 (SMS2), exhibiting inverted light-dependence compared to their extended analogs.
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