California Institute of Technology

University of Massachusetts

University of Washington

Other

University of California

City of Hope

Allozyne, Inc.

David A Tirrell

Allan Sachs Hoffman

Patrick S Stayton

Niren Murthy

Lawrence A Crum

Pierre D Mourad

Oliver Press

Inchan Kwon

Tyrone M Porter

Yi Tang

Pin Wang

Chantal Lackey Reed

Kristi Lynn Kiick

Robert H Grubbs

Daniel M Schwartz

Soojin Son

Paul J Nowatzki

Mark E Davis

Kenneth H Grabstein

Kevin Peter McGrath

Stephen L Mayo

Barbara J Wold

Howard Zisser

Deepshikha Datta

Isaac Carrico

Chantal Lackey

Kent Kirshenbaum

John F Murphy

Hsun Ku

Katharine Y Fang

Seth Lieblich

Wendy A Petka

Erin Schuman

Daniela C Dieterich

Aaron J Link

In some aspects, the invention relates to an insulin derivative, comprising a cyclic amino acid at position B28 or B29, wherein the cyclic amino acid is not L-proline. In some aspects, the invention relates to a method of making said insulin derivative. In some aspects, the invention relates to a pharmaceutical composition comprising said insulin derivative. In some aspects the invention relates to a method of treating a disease or condition in a subject comprising administering to the subject a composition comprising said insulin derivative.

Non-canonical insulins and their uses

The invention provides compositions and methods of identifying, modifying and producing modified target molecules, including therapeutic molecules by modification with non-natural amino acids. Certain aspects of the invention include methods of adding a chemical moiety to a target molecule, and the compositions resulting therefrom. Certain aspects of the invention also relate to kits for identifying, modifying and producing modified target molecules described herein.

Amino acid substituted molecules

In some embodiments, methods for improving the survival of pancreatic &#x3b2;-cell progenitors in culture are provided. Such methods may include contacting a population of pancreatic progenitor cells with an amino acid (aa) sequence comprising IKVAV (SEQ ID NO:1). In other embodiments, methods for (i) verifying the establishment of a population of pancreatic progenitor or stem cells and (ii) methods for generating or establishing a population of pancreatic endocrine progenitor cells in vitro are provided.

Methods for establishing and improving the survival of a population of pancreatic progenitor or stem cells

The invention provides a method of incorporating nonstandard amino acids into a protein by utilizing a modified aminoacyl-tRNA synthetase to charge the nonstandard amino acid to a modified tRNA, which forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with natural tRNAs.

Methods of incorporating amino acid analogs into proteins

The invention provides certain embodiments relating to methods and compositions for incorporating non-natural amino acids into a polypeptide or protein by utilizing a mutant or modified aminoacyl-tRNA synthetase to charge the non-natural amino acid to a the corresponding tRNA. In certain embodiments, the tRNA is also modified such that the complex forms strict Watson-Crick base-pairing with a codon that normally forms wobble base-pairing with unmodified tRNA/aminoacyl-tRNA synthetase pairs.

Site-specific incorporation of amino acids into molecules

Compositions and methods for transport or release of therapeutic and diagnostic agents or metabolites or other analytes from cells, compartments within cells, or through cell layers or barriers are described. The compositions include a membrane barrier transport enhancing agent and are usually administered in combination with an enhancer and/or exposure to stimuli to effect disruption or altered permeability, transport or release. In a preferred embodiment, the compositions include compounds which disrupt endosomal membranes in response to the low pH in the endosomes but which are relatively inactive toward cell membranes, coupled directly or indirectly to a therapeutic or diagnostic agent. Other disruptive agents can also be used, responsive to stimuli and/or enhancers other than pH, such as light, electrical stimuli, electromagnetic stimuli, ultrasound, temperature, or combinations thereof. The compounds can be coupled by ionic, covalent or H bonds to an agent to be delivered or to a ligand which forms a complex with the agent to be delivered. Agents to be delivered can be therapeutic and/or diagnostic agents. Treatments which enhance delivery such as ultrasound, iontopheresis, and/or electrophoresis can also be used with the disrupting agents.

Enhanced transport using membrane disruptive agents

The present invention provides engineered proteins and biomedical products made from the engineered proteins. The biomedical products include lenses useful for ophthalmic purposes.

Engineered proteins, and methods of making and using

Compositions and methods for transport or release of therapeutic and diagnostic agents or metabolites or other analytes from cells, compartments within cells, or through cell layers or barriers are described. The compositions include a membrane barrier transport enhancing agent and are usually administered in combination with an enhancer and/or exposure to stimuli to effect disruption or altered permeability, transport or release. In a preferred embodiment, the compositions include compounds which disrupt endosomal membranes in response to the low pH in the endosomes but which are relatively inactive toward cell membranes, coupled directly or indirectly to a therapeutic or diagnostic agent. Other disruptive agents can also be used, responsive to stimuli and/or enhancers other than pH, such as light, electrical stimuli, electromagnetic stimuli, ultrasound, temperature, or combinations thereof. The compounds can be coupled by ionic, covalent or H bonds to an agent to be delivered or to a ligand which forms a complex with the agent to be delivered. Agents to be delivered can be therapeutic and/or diagnostic agents. Treatments which enhance delivery such as ultrasound, iontophoresis, and/or electrophoresis can also be used with the disrupting agents.

Methods for producing modified polypeptides containing amino acid analogues are disclosed. The invention further provides purified dihydrofolate reductase polypeptides, produced by the methods of the invention, in which the methionine residues have been replaced with homoallylglycine, homoproparglycine, norvaline, norleucine, cis-crotylglycine, trans-crotylglycine, 2-aminoheptanoic acid, 2-butynylglycine and allylglycine.

Overexpression of aminoacyl-tRNA synthetases for efficient production of engineered proteins containing amino acid analogues

The present invention provides a microarray having one or more fusion proteins non-covalently attached to a solid support. Non-covalent attachment is achieved by designing a fusion protein having a polyanionic domain attached to a subject protein, and attaching the fusion protein to a solid support having a polycationic coating.

Fusion protein microarrays and methods of use

The present invention provides a method for producing modified stable polypeptides introducing at least one non-natural amino acid into the hydrophobic region of the polypeptide. The thermal and chemical stability of such polypeptides is improved compared to those properties of its corresponding wild type proteins. The invention further provides purified leucine zipper and coiled-coil proteins in which the leucine residues have been replaced with 5,5,5-trifluoroleucines, and the modified proteins so produced demonstrate increased thermal and chemical stability compared to their corresponding wild-type natural proteins.

Method for stabilization of proteins using non-natural amino acids

Compositions and methods for transport or release of therapeutic and diagnostic agents or metabolites or other analytes from cells, compartments within cells, or through cell layers or barriers are described. The compositions include a membrane barrier transport enhancing agent and are usually administered in combination with an enhancer and/or exposure to stimuli to effect disruption or altered permeability, transport or release. In a preferred embodiment, the compositions include compounds which disrupt endosomal membranes in response to the low pH in the endosomes but which are relatively inactive toward cell membranes, coupled directly or indirectly to a therapeutic or diagnostic agent. Other disruptive agents can also be used, responsive to stimuli and/or enhancers other than pH, such as light, electrical stimuli, electromagnetic stimuli, ultrasound, temperature, or combinations thereof. The compounds can be coupled by ionic, covalent or H bonds to an agent to be delivered or to a ligand which forms a complex with the agent to be delivered. Agents to be delivered can be therapeutic and/or diagnostic agents. Treatments which enhance delivery such as ultrasound, iontopheresis, and/or electrophereis can also be used with the disrupting agents.

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Pasadena, CA, United States of America

David A Tirrell