Screening methods using G-protein coupled receptors and related compositions
AssigneesThe General Hospital Corporation, Chugai Pharmaceutical Co., Ltd.
InventorsThomas J. Gardella, John T. Potts, Jr., Masaru Shimizu, Fumihiko Ichikawa, Harald Jüppner, Makoto Okazaki
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Abstract
The present invention provides screening methods for GPCRs based on the discovery that the affinity of a receptor agonist for a GPCR (such as the parathyroid hormone receptor) when not bound to a G-protein is correlated with the length of time over which the agonist is effective, independently of its pharmacokinetic properties. The invention also provides PTH- and PTHrP-derived polypeptides.
Claims28
A method for identifying a candidate compound as a long-acting agonist of a secretin family receptor, said method comprising:
- (a) contacting said secretin family receptor with said compound, wherein said secretin family receptor is in the RG form;
- (b) measuring the affinity of said compound for the RG form of said secretin family receptor;
- (c) contacting said secretin family receptor with said compound, wherein said secretin family receptor is in the R0 form;
- (d) measuring the affinity of said compound for the R0 form of said secretin family receptor;
- and
- (e) identifying said compound as a long-acting agonist of said secretin family receptor if said compound
- (i) has an affinity for the RG form of said secretin family receptor that is at least 10% of the affinity of an endogenous agonist for the RG form of said secretin family receptor, and
- (ii) has a greater affinity for the R0 form of said secretin family receptor than the affinity of said endogenous agonist for the R0 form of said secretin family receptor.
A method for identifying a candidate compound as a short-acting agonist of a secretin family receptor, said method comprising:
- (a) contacting said secretin family receptor with said compound, wherein said secretin family receptor is in the RG form;
- (b) measuring the affinity of said compound for the RG form of said secretin family receptor;
- (c) contacting said secretin family receptor with said compound, wherein said secretin family receptor is in the R0 form;
- (d) measuring the affinity of said compound for the R0 form of said secretin family receptor;
- and
- (e) identifying said compound as a short-acting agonist of said secretin family receptor if said compound
- (i) has an affinity for the RG form of said secretin family receptor that is at least 10% of the affinity of an endogenous agonist for the RG form of said GPCR, and
- (ii) has a lower affinity for the R0 form of said secretin family receptor than the affinity of said endogenous agonist for the R0 form of said secretin family receptor.
Dependencies are inferred from the claim text.