title: Rational design of a protein that binds integrin αvβ3 outside the ligand binding site.
abstract: Integrin αvβ3 expression is altered in various diseases and has been proposed as a drug target. Here we use a rational design approach to develop a therapeutic protein, which we call ProAgio, that binds to integrin αvβ3 outside the classical ligand-binding site. We show ProAgio induces apoptosis of integrin αvβ3-expressing cells by recruiting and activating caspase 8 to the cytoplasmic domain of integrin αvβ3. ProAgio also has anti-angiogenic activity and strongly inhibits growth of tumour xenografts, but does not affect the established vasculature. Toxicity analyses demonstrate that ProAgio is not toxic to mice. Our study reports a new integrin-targeting agent with a unique mechanism of action, and provides a template for the development of integrin-targeting therapeutics.
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Ravi Chakra
authors.identifier: 0000-0001-9075-7645
authors.initials: RC
authors.lastname: Turaga
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Lu
authors.initials: L
authors.lastname: Yin
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Yang
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Hsiauwei
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Ivaylo
authors.initials: I
authors.lastname: Ivanov
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Chunli
authors.initials: C
authors.lastname: Yan
authors.affiliation: Department of Ophthalmology, Eye Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Ophthalmology, Eye Center, Emory University, Atlanta, Georgia 30322, USA.
authors.forename: Hans E
authors.initials: HE
authors.lastname: Grossniklaus
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Siming
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Ma
authors.affiliation: Center for Diagnostics and Therapeutics, Amoytop Biotech Inc., Xiamen 361028, China.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Biology, Georgia State University, Atlanta, Georgia 30303, USA.
authors.forename: Zhi-Ren
authors.initials: ZR
authors.lastname: Liu
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D015195:Drug Design; D005260:Female; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D011485:Protein Binding / Q000235:genetics; D015202:Protein Engineering / Q000379:methods; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D008024:Ligands