title: Drug target validation: lethal infection blocked by inducible peptide.
abstract: Genome projects are generating large numbers of potential new targets for drug discovery. One challenge is target validation, proving the usefulness of a specific target in an animal model. In this paper, we demonstrate a new approach to validation and assay development. We selected in vitro specific peptide binders to a potential pathogen target. By inducing the expression of a selected peptide in pathogen cells causing a lethal infection in mice, the animals were rescued. Thus, by combining in vitro selection methods for peptide binders with inducible expression in animals, the target's validity was rigorously tested and demonstrated. This approach to validation can be generalized and has the potential to become a valuable tool in the drug discovery process.
authors.affiliation: Cubist Pharmaceuticals, Inc., 24 Emily Street, Cambridge, MA 02139, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tao
authors.forename: P
authors.initials: P
authors.lastname: Wendler
authors.forename: G
authors.initials: G
authors.lastname: Connelly
authors.forename: A
authors.initials: A
authors.lastname: Lim
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: King
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.forename: J A
authors.initials: JA
authors.lastname: Silverman
authors.forename: P R
authors.initials: PR
authors.lastname: Schimmel
authors.forename: F P
authors.initials: FP
authors.lastname: Tally
mesh_terms: D000595:Amino Acid Sequence; D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001424:Bacterial Infections / Q000401:mortality / Q000517:prevention & control*; D001435:Bacteriophages; D004195:Disease Models, Animal; D015195:Drug Design; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D018014:Gene Transfer Techniques; D005982:Glutathione Transferase / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D019151:Peptide Library; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015996:Survival Rate; D013754:Tetracyclines / Q000494:pharmacology
chemical_list: D009842:Oligopeptides; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D013754:Tetracyclines; C016229:4-epianhydrotetracycline; D005982:Glutathione Transferase; D000604:Amino Acyl-tRNA Synthetases; C100134:prolyl T RNA synthetase