title: Engineered adenovirus fiber shaft fusion homotrimer of soluble TRAIL with enhanced stability and antitumor activity.
abstract: Successful cancer therapies aim to induce selective apoptosis in neoplastic cells. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered an attractive anticancer agent due to its tumor cell-specific cytotoxicity. However, earlier studies with recombinant TRAIL revealed many shortcomings, including a short half-life, off-target toxicity and existence of TRAIL-resistant tumor cells. In this study, we developed a novel engineering strategy for recombinant soluble TRAIL by redesigning its structure with the adenovirus knobless fiber motif to form a stable homotrimer with improved antitumor activity. The result is a highly stable fiber-TRAIL fusion protein that could form homotrimers similar to natural TRAIL. The recombinant fusion TRAIL developed here displayed high specific activity in both cell-based assays in vitro and animal tests in vivo. This construct will serve as a foundation for a new generation of recombinant proteins suitable for use in preclinical and clinical studies and for effective combination therapies to overcome tumor resistance to TRAIL.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: R
authors.initials: R
authors.lastname: Zhu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: J
authors.initials: J
authors.lastname: Bi
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: J
authors.initials: J
authors.lastname: Wu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: H
authors.initials: H
authors.lastname: Wu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: B
authors.initials: B
authors.lastname: Yu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.|Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: W
authors.initials: W
authors.lastname: Kong
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, Jilin, China.|Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, Jilin, China.
authors.forename: X
authors.initials: X
authors.lastname: Yu
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D005818:Genetic Engineering; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055503:Protein Multimerization; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D012995:Solubility; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000737:chemistry / Q000302:isolation & purification / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand