title: Enhancement of antitumor properties of rhTRAIL by affinity increase toward its death receptors.
abstract: Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent and selective inducer of apoptosis in various tumor types, raising enthusiasm for TRAIL as a potential anticancer agent. TRAIL-induced apoptosis is mediated by death receptors 4 (DR4) and DR5. The design of rhTRAIL variants either with improved affinity or selectivity toward one or both death-inducing receptors is thought to enhance the therapeutical potential of TRAIL. Here we demonstrate that a single amino acid mutation at the position of glycine 131 to lysine or arginine in wild-type rhTRAIL significantly improved the affinity of rhTRAIL toward its death receptors, with the highest affinity increase observed for the DR4 receptor. These variants were able to induce higher in vitro levels of apoptosis in cancer cells responsive to only DR4 or to both death receptors and could therefore increase the potential use of rhTRAIL as an anticancer therapeutic agent.
authors.affiliation: Department of Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands.
authors.forename: Carlos R
authors.initials: CR
authors.lastname: Reis
authors.forename: Almer M
authors.initials: AM
authors.lastname: van der Sloot
authors.forename: Eva
authors.initials: E
authors.lastname: Szegezdi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Natoni
authors.forename: Vicente
authors.initials: V
authors.lastname: Tur
authors.forename: Robbert H
authors.initials: RH
authors.lastname: Cool
authors.forename: Afshin
authors.initials: A
authors.lastname: Samali
authors.forename: Luis
authors.initials: L
authors.lastname: Serrano
authors.forename: Wim J
authors.initials: WJ
authors.lastname: Quax
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000737:chemistry / Q000235:genetics; D001667:Binding, Competitive; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D030562:Databases, Protein; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D005998:Glycine / Q000737:chemistry / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D008239:Lysine / Q000737:chemistry / Q000235:genetics; D008958:Models, Molecular; D010447:Peptide Hydrolases / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D015853:Cysteine Proteinase Inhibitors; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D001120:Arginine; D010447:Peptide Hydrolases; C505530:CASP8 protein, human; D053148:Caspase 3; D053181:Caspase 8; C108711:DEVDase; D008239:Lysine; D005998:Glycine