Praecis Pharmaceuticals, Inc.

Howard Benjamin

Malcolm L Gefter

Ethan R Signer

Mark A Findeis

Arvind Hundal

Gary Fred Musso

Marc B Garnick

James Wakefield

Laura Kasman

Michael J Reed

Michael Kelley

David I Israel

Susan Molineaux

Joseph Chin

Jung-Ja Lee

William Kubasek

Alicia Peticolas

Farah Natoli

Kuanghui Lu

Martin P Keough

William Goodwin

Ling Chai

Compounds that modulate the aggregation of amyloidogenic proteins or peptides are disclosed. The modulators of the invention can promote amyloid aggregation or, more preferably, can inhibit natural amyloid aggregation. In a preferred embodiment, the compounds modulate the aggregation of natural &#x3b2; amyloid peptides (&#x3b2;-AP). In a preferred embodiment, the &#x3b2; amyloid modulator compounds of the invention are comprised of an A&#x3b2; aggregation core domain and a modifying group coupled thereto such that the compound alters the aggregation or inhibits the neurotoxicity of natural &#x3b2; amyloid peptides when contacted with the peptides. Furthermore, the modulators are capable of altering natural &#x3b2;-AP aggregation when the natural &#x3b2;-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Modulators of amyloid aggregation

An anchor library is described. A collection of recombinant vectors having a nucleic acid encoding a displayed peptide sequence is provided. The displayed peptide sequence of each of the vectors comprises X (Y ) X (Y ) X (Y ) X , wherein each X , X , X and X is an amino acid residue and any of X , X , X and X can be the same or different from any one other, wherein each Y , Y and Y is alanine or glycine or a combination of alanine and glycine that is respectively c , c and c amino acid residues long and any of Y , Y and Y if present can be the same or different from any one other, wherein each of c , c and c is 0 to about 20, wherein X and X are each attached to an amino acid residue that flanks the displayed peptide sequence. Preferably, at least about 10 to about 10 permutations of all possible permutations of the displayed peptide sequence are present in the anchor library. Preferably, the library does not contain more than about 10% of displayed peptide sequences different from the first mentioned displayed peptide sequences. Also described are methods of making anchor libraries and methods of using anchor libraries to identify a peptide sequence that binds to a target. Recombinant vectors, filamentous phage, nucleic acid molecules and proteins are also provided.

Anchor libraries and identification of peptide binding sequences

Compounds that modulate the aggregation of amyloidogenic proteins or peptides are disclosed. The modulators of the invention can promote amyloid aggregation or, more preferably, can inhibit natural amyloid aggregation. In a preferred embodiment, the compounds modulate the aggregation of natural &bgr; amyloid peptides (&bgr;-AP). In a preferred embodiment, the &bgr; amyloid modulator compounds of the invention are comprised of an A&bgr; aggregation core domain and a modifying group coupled thereto such that the compound alters the aggregation or inhibits the neurotoxicity of natural &bgr; amyloid peptides when contacted with the peptides. Furthermore, the modulators are capable of altering natural &bgr;-AP aggregation when the natural &bgr;-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

This invention provides peptide compounds that bind to either a fibroblast growth factor (FGF) or a fibroblast growth factor receptor (FGFR) and, accordingly, are useful for modulating FGFR activity. Preferably, the FGFR is FGFR2-IIIC. Preferably, the FGF is basic FGF. Preferably the peptide compound comprises an amino acid sequence: (Y/F)-(L/F/I)-(R/D/E/S/Y/G)-(Q/L/Y)-Y-(M/L/K/R)-(L/M/D/E/N/S)-(R/L/S/T)-(L/F/M/V) (SEQ ID NO: 1). The invention further comprises pharmaceutical compositions comprising the peptide compounds of the invention and a pharmaceutically acceptable carrier. The invention still further provides methods of modulating FGFR activity using the peptide compounds of the invention.

Peptide compounds useful for modulating FGF receptor activity

Compounds that modulate the aggregation of amyloidogenic proteins or peptides are disclosed. The modulators of the invention can promote amyloid aggregation or, more preferably, can inhibit natural amyloid aggregation. In a preferred embodiment, the compounds modulate the aggregation of natural .beta. amyloid peptides (.beta.-AP). In a preferred embodiment, the .beta. amyloid modulator compounds of the invention are comprised of an A.beta. aggregation core domain and a modifying group coupled thereto such that the compound alters the aggregation or inhibits the neurotoxicity of natural .beta. amyloid peptides when contacted with the peptides. Furthermore, the modulators are capable of altering natural .beta.-AP aggregation when the natural .beta.-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

A.beta. peptides that modulate .beta.-amyloid aggregation

Compounds that act to modulate the aggregation of natural .beta. amyloid peptides (.beta.-AP) are disclosed. The .beta. amyloid modulators of the invention can promote .beta.-AP aggregation or, more preferably, can inhibit natural .beta.-AP aggregation. Furthermore, the modulators are capable of altering natural .beta.-AP aggregation when the natural .beta.-APs are in a molar excess amount relative to the modulators. Pharmaceutical compositions comprising the compounds of the invention, and methods of altering natural .beta.-AP aggregation using the compounds of the invention, are also disclosed.

Modulators of .beta.-amyloid peptide aggregation

Compounds that act to modulate the aggregation of natural .beta. amyloid peptides (.beta.-AP) are disclosed. The .beta. amyloid modulators of the invention can promote .beta.-AP aggregation or, more preferably, can inhibit natural .beta.-AP aggregation. Furthermore, the modulators are capable of altering natural .beta.-AP aggregation when the natural .beta.-APs are in a molar excess amount relative to the modulators. Preferred .beta. amyloid modulators comprise amino-terminally biotinylated .beta. amyloid peptide compounds. Pharmaceutical compositions comprising the compounds of the invention, and methods of altering natural .beta.-AP aggregation using the compounds of the invention, are also disclosed.

Modulators of beta-amyloid peptide aggregation

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Lexington, MA, United States of America

Howard Benjamin