Abstract: The present invention includes methods of improving proteolytic stability of a polypeptide, comprising alkylating at least one selected from the group consisting of a N-terminus amino group, the NH group of the N-terminus first internal amide bond, another primary amino group, a thiol group and a thioether group within the polypeptide. The present invention further includes polypeptides incorporating such chemical modifications.

Abstract: The present invention includes peptidomimetic compound compositions and methods of making and using peptidomimetic compounds to modulate the activity of a peptide receptor for the treatment of one or more of hyperglycemia, insulin resistance, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia or other symptoms that relate to the function of the targeted receptor. The peptidomimetic includes an oligo-benzamide compound having at least three optionally substituted benzamides.

Abstract: The present invention includes peptidomimetic compound compositions and methods of making and using peptidomimetic compounds to modulate the activity of a peptide receptor for the treatment of one or more of hyperglycemia, insulin resistance, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia or other symptoms that relate to the function of the targeted receptor. The peptidomimetic includes an oligo-benzamide compound having at least three optionally substituted benzamides.

Abstract: GLP-1 fragments and derivatives thereof are able to interact with and activate the GLP-1 receptor GLP-1 fragments and derivatives thereof are used either alone or in combination with other pharmaceuticals in the treatment of type 1 and type 2 diabetes and other pathologies that are known to benefit from activation of the glucagon-like peptide-1 receptor.

Abstract: The present invention includes peptidomimetic compound compositions and methods of making and using peptidomimetic compounds to modulate the activity of a peptide receptor for the treatment of one or more of hyperglycemia, insulin resistance, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia or other symptoms that relate to the function of the targeted receptor. The peptidomimetic includes an oligo-benzamide compound having at least three optionally substituted benzamides.

Abstract: The present invention provides an alternative strategy for optimizing the signal to noise ratio of a given receptor. Specifically, the present invention provides receptor mutants having an increased signal to noise ratio. In one preferred embodiment, the present invention provides receptor mutants having a decreased level of basal activity. As part of this aspect, the present invention provides a mutant serotonin receptor and a mutant CCR-3 receptor, each having decreased basal activity. In another preferred embodiment, the present invention provides receptor mutants having an increased maximal level of ligand induced signaling. Such receptors optimize the signal to noise ratio of a receptor and provide, for example, for more sensitive screens for drug discovery.

Abstract: In general, the invention features methods that make use of animals expressing constitutively active G protein-coupled receptors for testing therapeutic efficacy and drug screening. Because these assays do not require animal breeding, they provide rapid assay results.

Abstract: The invention features a method for determining whether a candidate compound is a non-peptide agonist of a peptide hormone receptor. In this method, a candidate compound is exposed to a form of the peptide hormone receptor, or to a protein that interacts with a peptide hormone receptor, which has an enhanced ability to amplify the intrinsic activity of a non-peptide agonist. The second messenger signaling activity of the enhanced receptor is measured in the presence of the candidate compound, and compared to the second messenger signaling activity of the wildtype receptor measured in the absence of the candidate compound. A change in second messenger signaling activity indicates that the candidate compound is an agonist. An increase in second messenger signaling activity indicates that the compound is either a full or partial positive agonist; a decrease in second messenger signaling activity indicates that the compound is an inverse (also termed a ‘negative’) agonist.

Abstract: The invention features a method for determining whether a candidate compound is a non-peptide agonist of a peptide hormone receptor. In this method, a candidate compound is exposed to a form of the peptide hormone receptor which has an enhanced ability to amplify the intrinsic activity of a non-peptide agonist. The second messenger signaling activity of the enhanced receptor is measured in the presence of the candidate compound, and compared to the second messenger signaling activity of the enhanced receptor measured in the absence of the candidate compound. A change in second messenger signaling activity indicates that the candidate compound is an agonist. An increase in second messenger signaling activity indicates that the compound is either a full or partial positive agonist; a decrease in second messenger signaling activity indicates that the compound is an inverse (also termed a ‘negative’) agonist.

Abstract: The invention provides methods of identifying receptors having altered signaling. In particular, the invention provides a sensitive dose response assay for the identification of receptors having alterations in ligand dependent or ligand independent signaling.

Abstract: The invention features a method for determining whether a candidate compound is a non-peptide agonist of a peptide hormone receptor. In this method, a candidate compound is exposed to a form of the peptide hormone receptor, or to a protein that interacts with a peptide hormone receptor, which has an enhanced ability to amplify the intrinsic activity of a non-peptide agonist. The second messenger signaling activity of the enhanced receptor is measured in the presence of the candidate compound, and compared to the second messenger signaling activity of the wildtype receptor measured in the absence of the candidate compound. A change in second messenger signaling activity indicates that the candidate compound is an agonist. An increase in second messenger signaling activity indicates that the compound is either a full or partial positive agonist; a decrease in second messenger signaling activity indicates that the compound is an inverse (also termed a ‘negative’) agonist.

Abstract: The invention provides methods of identifying receptors having altered signaling. In particular, the invention provides a sensitive dose response assay for the identification of receptors having alterations in ligand dependent or ligand independent signaling.

Abstract: The invention features nucleic acids encoding constitutively active, hypersensitive, or nonfunctional receptors as novel therapeutic agents. The invention also features a method of treating a mammal, preventing a disease or disorder, or improve health by administering nucleic acids encoding constitutively active, hypersensitive, or nonfunctional receptors.

Abstract: The present invention provides methods of identifying receptors having altered signaling. In particular, the present invention provides an assay for the identification of receptors having alterations in ligand dependent or ligand independent signaling. Receptors having alterations in ligand dependent signaling that can be identified by the inventive method include hypersensitive hyposensitive receptors and receptors having increased or decreased potency. The inventive method is also applicable to the identification of receptors having alterations in basal activity, for example, constitutively active receptors or receptors having silencing mutations. Further applications include the identification of polymorphic or mutant receptors having alterations in signaling and receptors having an altered drug response. Finally, the receptors identified are useful as tools for drug discovery.

Abstract: The invention features a method for determining whether a candidate compound is a non-peptide agonist of a peptide hormone receptor. In this method, a candidate compound is exposed to a form of the peptide hormone receptor which has an enhanced ability to amplify the intrinsic activity of a non-peptide agonist. The second messenger signaling activity of the enhanced receptor is measured in the presence of the candidate compound, and compared to the second messenger signaling activity of the enhanced receptor measured in the absence of the candidate compound. A change in second messenger signaling activity indicates that the candidate compound is an agonist. An increase in second messenger signaling activity indicates that the compound is either a full or partial positive agonist; a decrease in second messenger signaling activity indicates that the compound is an inverse (also termed a ‘negative’) agonist.

Abstract: The invention features a method for determining whether a candidate compound is a non-peptide agonist of a peptide hormone receptor. In this method, a candidate compound is exposed to a form of the peptide hormone receptor which has an enhanced ability to amplify the intrinsic activity of a non-peptide agonist. The second messenger signaling activity of the enhanced receptor is measured in the presence of the candidate compound, and compared to the second messenger signaling activity of the enhanced receptor measured in the absence of the candidate compound. A change in second messenger signaling activity indicates that the candidate compound is an agonist. An increase in second messenger signaling activity indicates that the compound is either a full or partial positive agonist; a decrease in second messenger signaling activity indicates that the compound is an inverse (also termed a `negative`) agonist.