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Modular Pore-Forming Immunotoxins with Caged Cytotoxicity Tailored by Directed Evolution.
Mutter, Natalie L; Soskine, Misha; Huang, Gang; Albuquerque, Inês S; Bernardes, Gonçalo J L; Maglia, Giovanni.
Afiliación
  • Mutter NL; Groningen Biomolecular Science & Biotechnology Institute , University of Groningen , 9747 AG , Groningen , The Netherlands.
  • Soskine M; Groningen Biomolecular Science & Biotechnology Institute , University of Groningen , 9747 AG , Groningen , The Netherlands.
  • Huang G; Groningen Biomolecular Science & Biotechnology Institute , University of Groningen , 9747 AG , Groningen , The Netherlands.
  • Albuquerque IS; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , Avenida Professor Egas Moniz , 1649-028 , Lisboa , Portugal.
  • Bernardes GJL; Instituto de Medicina Molecular, Faculdade de Medicina , Universidade de Lisboa , Avenida Professor Egas Moniz , 1649-028 , Lisboa , Portugal.
  • Maglia G; Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , United Kingdom.
ACS Chem Biol ; 13(11): 3153-3160, 2018 11 16.
Article en En | MEDLINE | ID: mdl-30278129
Immunotoxins are proteins containing a cell-targeting element linked to a toxin that are under investigation for next-generation cancer treatment. However, these agents are difficult to synthesize, chemically heterogeneous, expensive, and show toxicity toward healthy cells. In this work, we describe the synthesis and characterization of a new type of immunotoxin that showed exquisite selectivity toward targeted cells. In our construct, targeting molecules were covalently attached or genetically fused to oligomeric pore-forming toxins. The activity of the immunotoxin was then caged by fusing a soluble protein to the transmembrane domain and activated via cleavage with furin, which is a protease that is overexpressed in many cancer cells. During the several coupling steps, directed evolution allowed the efficient synthesis of the molecules in E. coli cells, as well as selection for further specificity toward targeted cells. The final construct showed no off-target activity, while acquiring an additional degree of specificity toward the targeted cells upon activation. The pore-forming toxins described here do not require internalization to operate, while the many protomeric subunits can be individually modified to refine target specificity.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tetrahidrofolato Deshidrogenasa / Proteínas Recombinantes de Fusión / Inmunotoxinas / Venenos de Cnidarios / Proteínas Citotóxicas Formadoras de Poros Límite: Animals / Humans Idioma: En Revista: ACS Chem Biol Año: 2018 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tetrahidrofolato Deshidrogenasa / Proteínas Recombinantes de Fusión / Inmunotoxinas / Venenos de Cnidarios / Proteínas Citotóxicas Formadoras de Poros Límite: Animals / Humans Idioma: En Revista: ACS Chem Biol Año: 2018 Tipo del documento: Article País de afiliación: Países Bajos Pais de publicación: Estados Unidos