Rapid Formation of Non‐canonical Phospholipid Membranes by Chemoselective Amide‐Forming Ligations with Hydroxylamines**

Author:

Chen Jiyue1ORCID,Brea Roberto J.2ORCID,Fracassi Alessandro1ORCID,Cho Christy J.1ORCID,Wong Adrian M.1ORCID,Salvador‐Castell Marta3ORCID,Sinha Sunil K.3ORCID,Budin Itay1ORCID,Devaraj Neal K.1ORCID

Affiliation:

1. Department of Chemistry and Biochemistry University of California, San Diego 9500 Gilman Drive, Natural Sciences Building La Jolla CA 92093 USA

2. Biomimetic Membrane Chemistry (BioMemChem) Group CICA—Centro Interdisciplinar de Química e Bioloxía Universidade da Coruña Rúa As Carballeiras 15701 A Coruña Spain

3. Department of Physics University of California, San Diego 9500 Gilman Drive, Building: Mayer Hall Addition 4561 La Jolla CA 92093 USA

Abstract

AbstractThere has been increasing interest in methods to generate synthetic lipid membranes as key constituents of artificial cells or to develop new tools for remodeling membranes in living cells. However, the biosynthesis of phospholipids involves elaborate enzymatic pathways that are challenging to reconstitute in vitro. An alternative approach is to use chemical reactions to non‐enzymatically generate natural or non‐canonical phospholipids de novo. Previous reports have shown that synthetic lipid membranes can be formed in situ using various ligation chemistries, but these methods lack biocompatibility and/or suffer from slow kinetics at physiological pH. Thus, it would be valuable to develop chemoselective strategies for synthesizing phospholipids from water‐soluble precursors that are compatible with synthetic or living cells Here, we demonstrate that amide‐forming ligations between lipid precursors bearing hydroxylamines and α‐ketoacids (KAs) or potassium acyltrifluoroborates (KATs) can be used to prepare non‐canonical phospholipids at physiological pH conditions. The generated amide‐linked phospholipids spontaneously self‐assemble into cell‐like micron‐sized vesicles similar to natural phospholipid membranes. We show that lipid synthesis using KAT ligation proceeds extremely rapidly, and the high selectivity and biocompatibility of the approach facilitates the in situ synthesis of phospholipids and associated membranes in living cells.

Funder

National Institutes of Health

Agencia Estatal de Investigación

National Science Foundation

Publisher

Wiley

Subject

General Chemistry,Catalysis

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