The Salk Institute for Biological Studies

Research Development Foundation

Roland Riek

Jean E Rivier

Wylie W Vale, Jr

Marilyn H Perrin

Jean E F Rivier

Jean Claude Reubi

Senyon Choe

Judit Erchegyi

Tarmo Roosild

Jason Greenwald

Grace Christy Rani Royappa

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

A class of integral membrane proteins, referred to as Mistic polypeptides, their variants, fusion proteins including a Mistic polypeptide domain, and nucleic acid molecules encoding Mistic polypeptides and Mistic fusion proteins are disclosed herein. Also described are methods of using Mistic polypeptides and Mistic fusion proteins to produce and/or isolate recombinant proteins (including without limitation classes of eukaryotic proteins that have previously been intractable to recombinant bacterial expression, such as, eukaryotic integral membrane proteins).

Compositions and methods for producing recombinant proteins

Analogs of SRIF which are selective for SSTR4 in contrast to the other cloned SRIF receptors are useful in determining tissue and cellular expression of the receptor SSTR4 and its biological role in regulating tumor growth. SRIF analog peptides, such as des-AA[Ala]-SRIF; des-AA[Aph]-SRIF, des-AA[Aph]Cbm-SRIF; des-AA[Tyr,Ala]-Cbm-SRIF, and des-AA[Tyr,CMe-L-2Nal]-SRIF, and counterparts incorporating D-Cysand/or D-Trpand/or Ala, bind with high affinity to the cloned human receptor SSTR4 and activate the receptor, but they do not bind with significant affinity to human SSTR1, SSTR2, SSTR3 or SSTR5. By incorporating an iodinated tyrosine in position-2 in these SSTR4-selective SRIF analogs, a labeled compound useful in drug-screening methods is provided. Alternatively, for use in therapy, cytotoxins or highly radioactive elements can be N-terminally coupled or complexed thereto.

Receptor(SSTR4)-selective somatostatin analogs

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La Jolla, CA, United States of America

Roland Riek