title: Targeted rescue of cancer-associated IDH1 mutant activity using an engineered synthetic antibody.
abstract: We have utilized a high-diversity phage display library to engineer antibody fragments (Fabs) that can modulate the activity of the enzyme isocitrate dehydrogenase 1 (IDH1). We show that a conformation-specific Fab can reactivate an IDH1 mutant associated with brain tumors. The results show that this strategy is a first step towards developing "activator drugs" for a large number of genetic disorders where mutations have disrupted protein function.
authors.affiliation: Department of Chemistry and Biochemistry, Indiana University South Bend, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, South Bend, Indiana, USA. srizk@iusb.edu.
authors.forename: Shahir S
authors.initials: SS
authors.lastname: Rizk
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Somnath
authors.initials: S
authors.lastname: Mukherjee
authors.affiliation: Perlmutter Cancer Cener, New York University Langone Medical Center, New York, USA.|Department of Medicine, New York University School of Medicine, New York, USA.
authors.forename: Akiko
authors.initials: A
authors.lastname: Koide
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.|Perlmutter Cancer Cener, New York University Langone Medical Center, New York, USA.|Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, USA.
authors.forename: Shohei
authors.identifier: http://orcid.org/0000-0001-5473-4358
authors.initials: S
authors.lastname: Koide
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Kossiakoff
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002384:Catalysis / Q000187:drug effects; D061505:Cell Surface Display Techniques; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D009154:Mutation; D019151:Peptide Library; D013816:Thermodynamics
chemical_list: D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D019151:Peptide Library; D007521:Isocitrate Dehydrogenase