title: Transitioning pharmacoperones to therapeutic use: in vivo proof-of-principle and design of high throughput screens.
abstract: A pharmacoperone (from "pharmacological chaperone") is a small molecule that enters cells and serves as molecular scaffolding in order to cause otherwise-misfolded mutant proteins to fold and route correctly within the cell. Pharmacoperones have broad therapeutic applicability since a large number of diseases have their genesis in the misfolding of proteins and resultant misrouting within the cell. Misrouting may result in loss-of-function and, potentially, the accumulation of defective mutants in cellular compartments. Most known pharmacoperones were initially derived from receptor antagonist screens and, for this reason, present a complex pharmacology, although these are highly target specific. In this summary, we describe efforts to produce high throughput screens that identify these molecules from chemical libraries as well as a mouse model which provides proof-of-principle for in vivo protein rescue using existing pharmacoperones.
authors.affiliation: Department of Internal Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, United States; Department of Cell Biology, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, United States. Electronic address: Michael.conn@ttuhsc.edu.
authors.forename: P Michael
authors.initials: PM
authors.lastname: Conn
authors.affiliation: Oregon Translational Research and Drug Development Institute (OTRADI), Portland, OR 97201, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Smithson
authors.affiliation: Translational Research Institute, Scripps Research Institute, Jupiter, FL 33458, United States.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hodder
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States; Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, United States.
authors.forename: M David
authors.initials: MD
authors.lastname: Stewart
authors.affiliation: Department of Genetics, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, United States.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.affiliation: Translational Research Institute, Scripps Research Institute, Jupiter, FL 33458, United States.
authors.forename: Emery
authors.initials: E
authors.lastname: Smith
authors.affiliation: Research Support Network, Instituto Nacional de Ciencias Medicas y Nutricion, S-Z Universidad Autonoma de Mexico, Mexico, D.F., Mexico.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Ulloa-Aguirre
authors.affiliation: Department of Internal Medicine, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, United States; Department of Cell Biology, Texas Tech University Health Science Center, 3601 4th Street, Lubbock, TX 79430, United States.
authors.forename: Jo Ann
authors.initials: JA
authors.lastname: Janovick
mesh_terms: D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D021381:Protein Transport / Q000187:drug effects; D011506:Proteins / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries
keywords: Animal models; High throughput screens; Pharmacoperone; Protein rescue; Protein trafficking; Therapeutic approaches