The General Hospital Corporation

Chugai Pharmaceutical Co.

Harald Jüppner

Thomas J Gardella

John T Potts, Jr

Henry M Kronenberg

F Richard Bringhurst

Makoto Okazaki

Masaru Shimizu

Fumihiko Ichikawa

David A Rubin

Paola Divieti

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.

Screening methods using G-protein coupled receptors and related compositions

Novel parathyroid hormone peptide (PTH) and parathyroid hormone related peptide (PTHrP) or derivatives thereof which are biologically active are disclosed, as are pharmaceutical compositions containing such peptides, and synthetic and recombinant methods for producing such peptides. Also disclosed are methods for treating mammalian conditions characterized by decreases in bone mass using therapeutically effective pharmaceutical compositions containing such peptides. Also disclosed are methods for screening candidate compounds of the invention for antagonistic or agonistic effects on parathyroid hormone receptor action. Also disclosed are diagnostic and therapeutic methods of such compounds.

Bioactive peptides and peptide derivatives of parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP)

The invention relates to a mammalian cell lacking type-1 parathyroid hormone (PTH)/parathyroid hormone-related peptide (PTHrP) receptor (PTH1R) activity and containing carboxyl-terminal parathyroid hormone receptor (CPTHR) activity. The invention also relates to a method of screening for agonists or antagonists for CPTHR.

PTH analogs for renal osteodystrophy and related uses

Novel parathyroid hormone (PTH) peptides and analogs thereof of the PTH(1&#x2013;34) fragment are disclosed that combine the N-terminal signaling domain (residues 1&#x2013;9) and the C-terminal binding domain (residues 15&#x2013;31) via a linker. Nucleic acid molecules and peptides for PTH(1&#x2013;9)-(Gly)5-PTH(15&#x2013;31) (PG5) and PTH(1&#x2013;9)-(Gly)7-PTH(15&#x2013;31) and a novel PTH receptor are disclosed. Additionally, methods of screening for PTH agonists, pharmaceutical compositions and methods of treatment are disclosed.

Nucleic acids encoding PTH functional domain conjugate peptides

The present invention relates to novel parathyroid hormone (PTH) and parathyroid hormone related protein (PTHrP) receptors (PTH1R and PTH3R) isolated from zebrafish. The receptors of the present invention share homology with previously identified parathyroid hormone (PTH)/parathyroid related protein (PTHrP) receptors. Isolated nucleic acid molecules are provided encoding the zebrafish PTH1R and PTH3R receptors. PTH1R and PTH3R receptor polypeptides are also provided, as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of PTH1R and PTH3R receptor activity and to diagnostic and therapeutic methods.

PTH1R receptors

Novel parathyroid hormone (PTH) peptides and analogs thereof of the PTH(1&#x2013;34) fragment are disclosed that combine the N-terminal signaling domain (residues 1&#x2013;9) and the C-terminal binding domain (residues 15&#x2013;31) via a linker. Nucleic acid molecules and peptides for PTH(1&#x2013;9)-(Gly)5-PTH(15&#x2013;31) (PG5) and (1&#x2013;9)-(Gly)7-PTH(15&#x2013;31) and a novel PTH receptor are disclosed. Additionally, methods of screening for PTH agonists, pharmaceutical compositions and methods of treatment are disclosed.

PTH functional domain conjugate peptides, derivatives thereof and novel tethered ligand-receptor molecules

Novel parathyroid hormone(PTH) polypeptide derivatives are disclosed, as are pharmaceutical compositions containing said polypeptides, and synthetic and recombinant methods for producing said polypeptides. Also disclosed are methods for treating mammalian conditions characterized by decreases in bone mass using therapeutically effective pharmaceutical compositions containing said polypeptides. Also disclosed are methods for screening candidate compounds of the invention for antagonistic or agonistic effects on parathyroid hormone receptor action. Also disclosed are diagnostic and therapeutic methods of said compounds.

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Cambridge, MA, United States of America

Harald Jüppner