Praecis Pharmaceuticals, Inc.

Immulogic Pharmaceutical Corporation

Glaxosmithkline LLC

Immulogic, Inc.

Merck Patent Gmbh

Immulogic Pharmacuetical Corp.

Malcolm L Gefter

Gary Fred Musso

Ethan R Signer

Marc B Garnick

Mark A Findeis

Christopher C Arico-Muendel

James Wakefield

Julia L Greenstein

Christopher J Molineaux

David I Israel

Howard Benjamin

Michael Kelley

Barry A Morgan

Richard W Wagner

Dennis R Benjamin

Malcolm J Kavarana

Matthew Clark

Stephen Paul Hale

Nils Jakob Vest Hansen

Raksha A Acharya

Joseph Chin

Susan Molineaux

Jung-Ja Lee

Arvind Hundal

George J Franklin

Barbara S Fox

Mark A Exley

Kathryn Phillips

Stephen P Powers

Paolo A Centrella

Victoria C Schad

Philip A Swain

Neil J Hayward

Michael J Reed

Laura Kasman

Richard D Garman

Steffen Phillip Creaser

Thomas J Briner

Sonja Komar-Panicucci

Mei-chang Kuo

Nicholas P Barker

Malcolm Morville

Jay Paul Morgenstern

Bruce L Rogers

Julian F Bond

Andrew W Brauer

Irwin J Griffith

Steffan Phillip Creaser

Nils Jakob Hansen

Ze'ev Shaked

William Kubasek

Sonja A Komar

Ze&prime;ev Shaked

Paulo A Centrella

Ling Chai

William Goodwin

Martin P Keough

Kuanghui Lu

Farah Natoli

Alicia Peticolas

Mathew A Clark

Nicholas Barker

The present invention provides a method of synthesizing libraries of molecules which include an encoding oligonucleotide tag.

Methods for synthesis of encoded libraries

Sustained delivery formulations comprising a water-insoluble complex of a peptide and a plurality of ligands are disclosed. The formulations of the invention allow for loading of high concentrations of peptide in a small volume and for delivery of a pharmaceutically active peptide for prolonged periods, e.g., one month, after administration of the complex. The complexes of the invention can be milled or crushed to a fine powder. In powdered form, the complexes form stable aqueous suspensions and dispersions, suitable for injection. Methods of making the complexes of the invention, and methods of these complexes are also disclosed.

Pharmaceutical compositions for sustained drug delivery

The present invention provides a method for identifying a compound of interest by screening libraries of molecules which include an encoding oligonucleotide tag.

Methods for identifying compounds of interest using encoded libraries

The present invention provides methods of synthesizing libraries of molecules comprising a functional moiety which is operatively linked to an encoding oligonucleotide, wherein the encoding oligonucleotide comprises a capping sequence containing degenerate nucleotides. The methods generally include providing a solution comprising initiator compounds comprising an initial functional moiety comprising n building blocks which is operatively linked to an initial oligonucleotide; dividing the solution into reaction vessels; reacting the initiator compounds in each reaction vessel with a building block comprising a complementary reactive group to form a covalent bond; and reacting the initial oligonucleotide in each aliquot with a distinct incoming oligonucleotide in the presence of an enzyme which catalyzes the ligation of the incoming oligonucleotide and the initial oligonucleotide, under conditions suitable for enzymatic ligation of the incoming oligonucleotide and the initial oligonucleotide to form an encoding oligonucleotide.

The present invention provides methods of synthesizing a molecule comprising a functional moiety which is operatively linked to an encoding oligonucleotide. The methods include providing an initiator compound comprising an initial functional moiety comprising n building blocks, wherein the initial functional moiety comprises at least one reactive group, and is operatively linked to an initial oligonucleotide; reacting the initiator compound with a building block comprising at least one complementary reactive group, under conditions suitable for reaction of the complementary reactive group to form a covalent bond; and reacting the initial oligonucleotide with an incoming oligonucleotide corresponding to the building block in the presence of an enzyme which catalyzes ligation of the initial oligonucleotide and the incoming oligonucleotide, under conditions suitable for ligation of the incoming oligonucleotide and the initial oligonucleotide to form an encoding oligonucleotide.

The present invention provides methods of synthesizing libraries of molecules comprising a functional moiety which is operatively linked to an encoding oligonucleotide. The methods generally include providing a solution comprising initiator compounds comprising an initial functional moiety which comprises n building blocks which comprise at least one reactive group, which is operatively linked to an initial oligonucleotide; dividing the solution into reaction vessels; reacting the initiator compounds in each reaction vessel with a building block comprising a complementary reactive group to form a covalent bond; and reacting the initial oligonucleotide in each aliquot with a distinct incoming oligonucleotide in the presence of an enzyme which catalyzes the ligation of the incoming oligonucleotide and the initial oligonucleotide, under conditions suitable for enzymatic ligation of the incoming oligonucleotide and the initial oligonucleotide to form an encoding oligonucleotide which identifies the structure of the functional moiety.

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

A substantially pure, covalently linked human T cell reactive feline protein (TRFP) has been isolated from vacuum bag extract obtained by affinity purification of house dust collected from several homes with cats; DNA encoding all or a portion of the TRFP or peptide; compositions containing such a protein or peptide or portions thereof; and antibodies reactive with the TRFP or peptide are disclosed. Also disclosed are recombinant TRFP or peptide; modified or mutated TRFP peptides; their use for diagnostic or therapeutic purposes.

Human T cell reactive feline protein (TRFP) isolated from house dust and uses therefor

Compounds that modulate natural &#x3b2; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &#x3b2; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3&#x2013;5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &#x3b2; amyloid peptide, preferably a retro-inverso isomer of A&#x3b2;. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. 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 &#x3b2;-amyloid peptide aggregation comprising D-amino acids

The present invention provides therapeutic compositions and methods for treating disease conditions in humans associated with an antigen specific immune response by the human to an antigen such as a protein antigen (i.e. allergy and autoimmune diseases). Therapeutic compositions of the invention are reproducible preparations which are suitable for human therapy. Compositions of the invention comprise at least one isolated peptide having a defined sequence of amino acid residues and the composition is capable of down regulating an antigen specific immune response to an offending antigen in a population of humans subject to the antigen specific immune response. Compositions and methods of the invention may be used to treat sensitivity to protein allergens in humans and may also be used to treat autoimmune disease such as rheumatoid arthritis, diabetes, myasthenia gravis, Grave's disease, Good Pasture's syndrome, thyroiditis and multiple sclerosis.

Compositions and methods for administering to humans, peptides capable of down regulating an antigen specific immune response

Sustained delivery formulations comprising a water-insoluble complex of a peptide and a carrier macromolecule are disclosed. The formulations of the invention allow for loading of high concentrations of peptide in a small volume and for delivery of a pharmaceutically active peptide for prolonged periods, e.g., one month, after administration of the complex. The complexes of the invention can be milled or crushed to a fine powder. In powdered form, the complexes form stable aqueous suspensions and dispersions, suitable for injection. In a preferred embodiment, the peptide of the complex is an LHRH analogue, preferably an LHRH antagonist, and the carrier macromolecule is an anionic polymer, preferably carboxymethylcellulose. Methods of making the complexes of the invention, and methods of using LHRH-analogue-containing complexes to treat conditions treatable with an LHRH analogue, are also disclosed.

Pharmaceutical formulations for sustained drug delivery

Compounds that modulate natural &bgr; amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a &bgr; amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a &bgr; amyloid peptide, preferably a retro-inverso isomer of A&bgr; . In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups include cyclic, heterocyclic, polycyclic and branched alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an alkyl amide group, an aryl amide group or a hydroxy group. 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 &bgr;-amyloid peptide aggregation comprising D-amino acids

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

Growing community of inventors

Lincoln, MA, United States of America

Malcolm L Gefter