title: Ligand-receptor interaction catalyzes the aggregation of small molecules to induce cell necroptosis.
abstract: Because they exhibit important biological functions, from unfolding proteins to activating enzymes to controlling cell fates, aggregates of small molecules are able to serve as functional molecular entities in cellular environments. However, the inability to precisely control their production has hampered the understanding and exploration of their biological functions. Here we show that the well-established ligand-receptor interaction between vancomycin and d-Ala-d-Ala catalyzes the aggregation of a d-Ala-d-Ala-containing small peptide derivative in water. The resulting aggregates largely adhere to the cell surface to induce cell necroptosis. Mutation of d-Ala-d-Ala to l-Ala-l-Ala or removal of the aromatic group in the derivative results in innocuous compounds, confirming that the aromatic-aromatic and ligand-receptor interactions are responsible for the formation and corresponding cytotoxicity of the aggregates. In addition to being the first example of ligand-receptor interaction-catalyzed aggregation of small molecules on the surface of mammalian cells, this work provides useful insights for understanding the cytotoxicity of molecular aggregates of small molecules.
authors.affiliation: Department of Chemistry, Brandeis University , 415 South Street, MS 015, Waltham, Massachusetts 02453, United States.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.forename: Xuewen
authors.initials: X
authors.lastname: Du
authors.forename: Yibing
authors.initials: Y
authors.lastname: Huang
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Dan
authors.initials: D
authors.lastname: Yuan
authors.forename: Dongdong
authors.initials: D
authors.lastname: Wu
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard
authors.initials: R
authors.lastname: Haburcak
authors.forename: Irving R
authors.initials: IR
authors.lastname: Epstein
authors.forename: Bing
authors.initials: B
authors.lastname: Xu
mesh_terms: D017209:Apoptosis; D055162:Biocatalysis / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D009336:Necrosis; D010455:Peptides / Q000737:chemistry*; D066329:Protein Aggregates / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013499:Surface Properties; D014640:Vancomycin / Q000737:chemistry* / Q000494:pharmacology*; D014867:Water / Q000737:chemistry
chemical_list: D004151:Dipeptides; D008024:Ligands; D010455:Peptides; D066329:Protein Aggregates; D014867:Water; C002956:alanylalanine; D014640:Vancomycin