Engineering of Saposin C Protein Chimeras for Enhanced Cytotoxicity and Optimized Liposome Binding Capability

Saposin C (sapC) is a lysosomal, peripheral-membrane protein displaying liposome fusogenic capabilities. Proteoliposomes of sapC and phosphatidylserine have been shown to be toxic for cancer cells are currently on clinical trial treat glioblastoma. As proof-of-concept, we show two strategies enhance the applications proteoliposomes: (1) Engineering chimeras composed modulate proteoliposome function; (2) modify its lipid binding In chimera design, linked cell death-inducing peptide: BH3 domain Bcl-2 PUMA. We by solution NMR dynamic light scattering that functional at molecular level fusing liposomes interacting with prosurvival Bcl-xL, which PUMA’s known mechanism induce death. Furthermore, sapC-PUMA proteoliposomes cytotoxicity in glioblastoma compared sapC. Finally, has engineered optimize pH close physiological values as protein–lipid interactions favored acidic native protein. Altogether, our results indicate properties can modified engineering surface addition small peptides fusion constructs.