University of Texas System

The Scripps Research Institute

Opko Pharmaceuticals, LLC

Opko Health, Inc.

Thomas Kodadek

Rolf A Brekken

Phillip Frost

D Gomika Udugamasooriya

Stephen Albert Johnston

Muralidhar Reddy Moola

Dwight German

Steven Connell

Mohosin Sarkar

Rosemary Wilson

Yu Gao

Johnnie Wilson

Yong-Uk Kwon

Glenn C Micalizio

David A Fancy

Reddy Moola

The present disclosure is directed to a novel class of peptide-like oligomers called peptide tertiary amides (PTAs) and a combinatorial library of PTAs along with synthetic routes for the preparation of large combinatorial libraries of these compounds. The peptide tertiary amides provide an exceptional source of high affinity and selective protein ligands that are useful as tools for biological research and as drug leads, among others.

Synthesis of libraries of peptide tertiary amides

Chiral oligomeric pentenoate amides are bio-oligomer mimetics possessing a high degree of conformation rigidity. Conformational rigidity is desirable in the design of molecules with high affinities for biological receptors and enzymes. Libraries of such oligomeric mimetics, such as of chiral oligomeric pentenoate amides can be used to probe biological systems. The present invention provides a method for preparation of chiral oligomeric pentanoate amides comprising conversion of a chiral oxazolidinone (4) to a chiral monomer of formula (1) which can be oligomerized to a chiral compound of formula (12) and so forth.

Chiral oligomeric pentenoate amides as bio-oligomer mimetics

The present invention provides for the identification of individuals having neurodegenerative diseases (ND). Peptoids recognized by Parkinson's Disease- and Alzheimer's Disease-specific antibodies are identified, allowing one to diagnose or predict ND in subjects.

Identification of small molecules recognized by antibodies in subjects with neurodegenerative diseases

The present invention provides for the identification of an antigen surrogate to the native antigens for the autoimmune disease pemphigus vulgaris. Ligands are discovered using large random peptoid or cyclic peptoid libraries that are screened against known antibodies to autoimmune diseases. The ligands may be useful as drugs in the treatment of such diseases and can also be used in combination with the comcomitant removal of T-cells associated with autoimmune disorders.

Antigen surrogates in autoimmune disease

A cell-based screen is reported can be used to identify specific receptor-binding compounds in a combinatorial library of peptoids (N-alkylglycine oligomers) displayed on beads. This strategy was applied to the isolation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2)-binding peptoids, which were optimized to create lead compounds with high affinity for VEGFR2. One of these peptoids was shown to be an antagonist of VEGF-VEGFR2 interaction and receptor function.

High affinity VEGF-receptor antagonists

Embodiments of the invention are directed to a one-bead-two-compound method for the creation of encoded cyclic peptoid libraries. This scheme is useful for the creation of cyclic peptoid microarrays since only the cyclic peptoid, not the linear encoding molecule, contains an attachment residue and thus can be spotted onto an activated substrate.

Compositions and methods for producing cyclic peptoid libraries

The present invention provides for the identification of an antigen surrogate to the native antigens for the autoimmune disease pemphigus vulgaris. Ligands are discovered using large random peptoid or cyclic peptoid libraries that are screened against known antibodies to autoimmune diseases. The ligands may be useful as drugs in the treatment of such diseases and can also be used in combination with the concomitant removal of T-cells associated with autoimmune disorders.

The present invention relates to methods and compositions for detecting a substance using mixed or multiple element capture agents (MECA). The affinity of a MECA for a target is produced by the concomitant binding of at least two low to moderate affinity capture agents providing a high affinity interaction with a capture target.

Methods and compositions comprising capture agents

The present invention provides a highly sensitive screening assay for the identification of peptide binding partners to virtually any peptide or polypeptide ligand. Utilizing an expression-repression readout system, the inventors have screened libraries of peptides and identified relatively small peptide molecules that bind to the provided target.

Selection of peptides with antibody-like properties

The present application describes novel uses of ruthenium bipyridyls or palladium porphyrins as photo-activatable crosslinking agents. Crosslinking can be between any two molecules including peptides, proteins, or compounds. Crosslinking occurs in the presence of an electron donor such as ammonium persulfate, and requires only moderate intensity visible light. Crosslinking can be between peptides, polypeptides or lead candidate compounds to unknown target molecules. Reagents utilyzing ruthenium bipyridyls and palladium porphyrins crosslinkers for use in diagnostic and detection scenarios are also disclosed.

Growing community of inventors

Jupiter, FL, United States of America

Thomas Kodadek