Biosynthesis of natural lipidated proteins is linked to important signal pathways, and therefore analyzing protein lipidation is crucial for understanding cellular functions. Artificial lipidation of proteins has attracted attention in recent decades as it allows modulation of the amphiphilic nature of the protein of interest, and is used in the design of drug‐delivery systems containing antibodies anchored on a lipid bilayer carrier. However, the intrinsic hydrophobicity of lipids makes the synthesis of lipid–protein conjugates challenging with respect to the yield and selectivity of the lipidation. In this Minireview, the development of chemical and enzymatic synthetic strategies for the preparation of a range of lipid–protein conjugates that do not compromise the functions of the proteins are discussed as well as applications of the conjugates.
Synthesis
of lipid–protein conjugates is one of the significant
techniques in drug delivery systems of proteins; however, the intact
conjugation of a lipid and protein is yet challenging due to the hydrophobicity
of lipid molecules. In order to facilitate easy handling of the lipid
moiety in conjugation, we have focused on a microbial transglutaminase
(MTG) that can ligate specific lysine (K) and glutamine (Q) residues
in lipopeptides and a protein of interest. As MTG substrates, monolipid-
and dilipid-fused amphiphilic short lipopeptide substrates (lipid-G3S-RHK or lipid2-KG3S-RHK) were designed.
These amphiphilic lipopeptides and a model protein (enhanced green
fluorescent protein, EGFP) fused with LLQG (LQ-EGFP) were both water-soluble,
and thus lipid–protein conjugates were efficiently obtained
through the MTG reaction with a >80% conversion rate of LQ-EGFP
even
using cholesterol-G3S-RHK. In vitro cell
adhesion and in vivo half-life stability of the successfully
obtained lipid–protein conjugates were evaluated, showing that
the monocholesterol-G3S-RHK modification of a protein gave
the highest cell adhesion efficiency and longest half-life time by
formation of a stable albumin/lipid–protein complex.
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