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Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity.
Johannes Morstein1,2, Alice Capecchi3, Konstantin Hinnah4
1Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, California 94158, United States.
Journal of the American Chemical Society
|September 30, 2022
Summary
Lipid conjugation, especially with medium-chain lipids (MCLs), enhances small molecule cell permeability and bioactivity. This strategy offers a powerful approach for designing novel chemical probes and drugs.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Chemical Biology
Background:
- Bioactive molecules often require membrane interaction for efficacy.
- Natural products frequently utilize lipid modifications for membrane interactions, impacting bioactivity.
- Lipid conjugation is underutilized in chemical biology and drug design.
Purpose of the Study:
- To characterize the "natural product lipidome" and understand natural lipid conjugation patterns.
- To systematically investigate the impact of lipid conjugation on small molecule properties for probe design.
- To evaluate medium-chain lipids (MCLs) as effective lipidating agents.
Main Methods:
- Chemoinformatic analysis of natural product lipid composition.
- Systematic exploration of lipid conjugation effects on five small molecule chemotypes.
- Comparative assessment of medium-chain lipid (MCL), long-chain lipid (LCL), and short-chain lipid (SCL) conjugates.
Main Results:
- Natural products predominantly feature saturated medium-chain lipids (MCLs), distinct from membrane lipids.
- MCL conjugation significantly modulated permeability, cellular retention, localization, and bioactivity of small molecules.
- MCL-conjugates consistently outperformed LCL-conjugates and showed comparable or superior performance to SCL-conjugates in uptake and bioactivity.
Conclusions:
- Medium-chain lipid (MCL) conjugation is a potent strategy to enhance small molecule cell permeability and bioactivity.
- This approach holds significant promise for the development of advanced chemical probes and therapeutic agents.
- Understanding natural lipid conjugation informs the design of novel synthetic lipidated molecules.
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