title: Mutants of listeriolysin O for enhanced liposomal delivery of macromolecules.
abstract: Delivery of macromolecules into the cytosolic space of eukaryotic cells is a pressing challenge in biopharmaceutics. Macromolecules are often encapsulated into liposomes for protection and improved distribution, but the their size often induces endocytosis of the vehicle at the target site, leading to degradation of the cargo. Listeriolysin O is a key virulence factor of Listeria monocytogenes that forms pores in the endosomal membrane, ultimately allowing the bacterium to escape into the cytosol. This function of LLO has been used to improve cytosolic delivery of liposomally encapsulated macromolecules in a number of instances, but its innate toxicity and immunogenicity have prevented it from achieving widespread acceptance. Through site-directed mutagenesis, this study establishes a mutant of LLO (C484S) with enhanced activity, allowing for a reduction in the amount of LLO used for future applications in liposomal drug delivery.
authors: Center for Molecular Drug Targeting CMDT, Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States. wallsz@etsu.edu
authors: Zachary F
authors: ZF
authors: Walls
authors: Stefanie
authors: S
authors: Goodell
authors: Chasity D
authors: CD
authors: Andrews
authors: Jonathan
authors: J
authors: Mathis
authors: Kyung-Dall
authors: KD
authors: Lee
mesh_terms: D001427:Bacterial Toxins / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics; D016000:Cluster Analysis; D016503:Drug Delivery Systems / Q000379:methods*; D006360:Heat-Shock Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics; D006460:Hemolysin Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000235:genetics / Q000493:pharmacokinetics; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D011487:Protein Conformation
chemical_list: D001427:Bacterial Toxins; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D008081:Liposomes; C038705:hlyA protein, Listeria monocytogenes