Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity.

Morstein, Johannes; Capecchi, Alice; Hinnah, Konstantin; Park, ByungUk; Petit-Jacques, Jerome; Van Lehn, Reid C; Reymond, Jean-Louis; Trauner, Dirk (2022). Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity. Journal of the American Chemical Society, 144(40), pp. 18532-18544. American Chemical Society 10.1021/jacs.2c07833

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Chemistry, Biochemistry and Pharmaceutical Sciences (DCBP)

UniBE Contributor:

Capecchi, Alice, Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

0002-7863

Publisher:

American Chemical Society

Language:

English

Submitter:

Pubmed Import

Date Deposited:

03 Oct 2022 10:35

Last Modified:

05 Dec 2022 16:25

Publisher DOI:

10.1021/jacs.2c07833

PubMed ID:

36178375

BORIS DOI:

10.48350/173419

URI:

https://boris.unibe.ch/id/eprint/173419

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