Peptidophospholipids: Synthesis, phospholipase A2 catalyzed hydrolysis, and application to development of phospholipid prodrugs

• Peptide conjugates of phospholipids have been prepared for the first time.
• The synthesis provides access to PLA2-directed prodrugs.
• The α-methylene group next to the sn-2-carboxyl is essential for PLA2-catalysis.
• New design principles developed for the synthesis of PLA2-targeted substrates.

New phospholipid analogues incorporating sn-2-peptide substituents have been prepared to probe the fundamental structural requirements for phospholipase A2 catalyzed hydrolysis of PLA2-directed synthetic substrates. Two structurally different antiviral oligopeptides with C-terminal glycine were introduced separately at the sn-2-carboxylic ester position of phospholipids to assess the role of the α-methylene group adjacent to the ester carbonyl in allowing hydrolytic cleavage by the enzyme. The oligopeptide-carrying phospholipid derivatives were readily incorporated into mixed micelles consisting of natural phospholipid (dipalmitoyl phosphatidylcholine, DPPC) and Triton X-100 as surfactant. Hydrolytic cleavage of the synthetic peptidophospholipids by the phospholipase A2 occurred slower, but within the same order of magnitude as the natural substrate alone. The results provide useful information toward better understanding the mechanism of action of the enzyme, and to improve the design and synthesis of phospholipid prodrugs targeted at secretory PLA2 enzymes.

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