The Salk Institute for Biological Studies

Research Development Foundation

University of Reading

University of California

The Scripps Research Institute

Scripps Clinic and Research Foundation

The Salk Institute of Biological Studies

Wylie W Vale, Jr

Jean E Rivier

Marilyn H Perrin

Catherine L Rivier

Kathy A Lewis

Joachim Spiess

Marvin R Brown

Jozsef Gulyas

Wolfgang H Fischer

Cynthia J Donaldson

Koichi Kunitake

Ruoping Chen

Paul Sawchenko

Joan Vaughan

Dominic P Behan

Jean E F Rivier

Philip J Lowry

Wayne D Kornreich

Jean-Francois Hernandez

Joan M Vaughan

Kunihiro Tsuchida

Francoise G Presse

Jean-Louis M Nahon

Elizabeth A Linton

Ellen Potter

Ronald Mark Evans

John S Porter

Michael G Rosenfeld

Carl A Hoeger

John B Hogenesch

Paula G Theobald

Paul E Sawchenko

Teresa M Reyes

Lawrence S Mathews

Arnold T Hagler

Mary P Stenzel-Poore

Max S Amoss

Lawrence W Mathews

Michael W Monahan

Nicholas C Ling

Roger C Guillemin

Frederick S Esch

Roger W Roeske

Kuo-Fen Lee

Shao-Yao Ying

George F Koob

Roland Riek

Harry A Anderson

Wolfgang Fischer

Steven C Koerber

Antonio De Miranda

Nancy M Sherwood

Michael J Brownstein

Stephen C Heinrichs

Larry Swanson

Janos I Varga

R Scott Struthers

Anne Corrigan

Kelly E Mayo

Gail Cerelli

Richard A McClintock

Lee E Eiden

Grace Christy Rani Royappa

Alice L Yu

Susan G Amara

John Yu

C Wayne Bardin

Robert A Rissman

Jean E River

Jeffrey Schwartz

Cindy Donaldson

Joan Vaughn

Jean F Hernandez

Koichi S Kunitake

Disclosed are polypeptides that are analogs of urocortin 2 that have pharmacological activity similar to urocortin 2 but have improved water solubility compared to urocortin 2, and pharmaceutical compositions of the polypeptides of the present invention. Also disclosed are polynucleotides encoding the polypeptides, and methods of treating pathophysiological states employing pharmaceutical compositions of the polypeptides and polynucleotides of the present invention. In addition, disclosed are vectors and host cells that include a nucleic acid encoding a polypeptide of the present invention, and kits that include pharmaceutical compositions of the present invention.

Urocortin 2 analogs and uses thereof

A search of the public human genome database identified a human EST, GenBank accession number AW293249, which has high homology to known pufferfish urocortin sequences. The full length sequence was amplified from human genomic DNA and sequenced. Sequence homology comparisons of the novel sequence with human urocortin I and urocortin II revealed that the sequence encoded a novel human urocortin, which was designated urocortin III (UcnIII). While urocortin III does not have high affinity for either CRF-R1 or CRF-R2, the affinity for CRF-R2 is greater than the affinity for CRF-R1. Urocortin III is capable stimulating cyclic AMP production in cells expressing CRF-R2&#x3b1; or &#x3b2;. Thus, the affinity is high enough that urocortin III could act as a native agonist of CRF-R2. However, it is also likely that urocortin III is a stronger agonist of a yet to be identified receptor.

Urocortin-III and uses thereof

A human urocortin-related peptide with significant sequence homology to the CRF neuropeptide family was identified. A mouse cDNA was isolated from whole brain poly (A+) RNA that encodes a predicted 38 amino acid peptide protein designated herein as urocortin II. Both human URP and mouse Ucn II are structurally related to the other known mammalian family members, CRF and urocortin (Ucn). These peptides are involved in the regulation of the hypothalamic-pituitary-adrenal axis under basal and stress conditions, suggesting a similar role for URP and Ucn IL Synthesized Ucn-II and URP peptide binds with higher affinity to CRF-R2 than to CRF-R1 Ucn II and human URP appear to be involved in the regulation of body temperature and appetite and may play a role in other stress related phenomenon. These findings identify Ucn II and human URP as a new members of the CRF family of neuropeptides, which are expressed centrally and bind to CRF-R2.

Urocortin proteins and uses thereof

In accordance with the present invention, there are provided novel receptor proteins characterized by having the following domains, reading from the N-terminal end of said protein:

Antibodies to activin receptor

The present invention relates to a method for identifying modulators of B1 G-protein coupled receptors. The present invention also relates to a method for identifying an antagonist or agonist of the corticotropin-releasing factor receptor 2 (CRFR2). The present invention also relates to a method for improving antagonists or agonists of CRFR2. The present invention also relates to the three-dimensional structure of CRFR2 as representative of the B1 GPCR subfamily and its use as a basis for rational drug design of antagonist or agonists of B1 GPCRs.

Structure-based modulators of B1 G-protein coupled receptors

CRF peptide analogs that bind to CRFR1 with an affinity far greater than they bind to CRFR2. Some of these analogs exhibit CRF agonist activity. One exemplary analog that may be made by solid-phase synthesis is: (cyclo 31-34)[Ac-Pro,D-Phe,Nle,Glu,Lys]-sucker urotensin(4-41).

CRFR1 selective ligands

In accordance with the present invention, there are provided novel G-protein-coupled receptor proteins (CRF-R) characterized by having sufficient binding affinity for corticotropin releasing factor (CRF) such that concentrations of &#xa3; 10 nM of CRF occupy50% of the binding sites of said receptor protein. Nucleic acid sequences encoding such receptors, assays employing same, as well as antibodies derived therefrom, are also disclosed. Invention CRF-Rs can be employed in a variety of ways, such as, for example, in bioassays, for production of antibodies thereto, in therapeutic compositions containing such proteins and/or antibodies.

Cloning and recombinant production of CRF receptor(s)

A human urocortin-related peptide with significant sequence homology to the CRF neuropeptide family was identified. A mouse cDNA was isolated from whole brain poly (A+) RNA that encodes a predicted 38 amino acid peptide protein designated herein as urocortin II. Both human URP and mouse Ucn II are structurally related to the other known mammalian family members, CRF and urocortin (Ucn). These peptides are involved in the regulation of the hypothalamic-pituituary-adrenal axis under basal and stress conditions, suggesting a similar role for URP and Ucn II. Synthesized Ucn-II and URP peptide binds with higher affinity to CRF-R2 than to CRF-R1 Ucn II and human URP appear to be involved in the regulation of body temperature and appetite and may play a role in other stress related phenomenon. These findings identify Ucn II and human URP as a new members of the CRF family of neuropeptides, which are expressed centrally and bind to CRF-R2.

Methods of screening for compounds that bind to activin receptor

A search of the public human genome database identified a human EST, GenBank accession number AW293249, which has high homology to known pufferfish urocortin sequences. The full length sequence was amplified from human genomic DNA and sequenced. Sequence homology comparisons of the novel sequence with human urocortin I and urocortin II revealed that the sequence encoded a novel human urocortin, which was designated urocortin III (UcnIII). While urocortin III does not have high affinity for either CRF-R1 or CRF-R2, the affinity for CRF-R2 is greater than the affinity for CRF-R1. Urocortin III is capable stimulating cyclic AMP production in cells expressing CRF-R2&agr; or &bgr;. Thus, the affinity is high enough that urocortin III could act as a native agonist of CRF-R2. However, it is also likely that urocortin III is a stronger agonist of a yet to be identified receptor.

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La Jolla, CA, United States of America

Wylie W Vale, Jr