California Institute of Technology

University of Rochester

Rudi Fasan

Frances H Arnold

Peter Meinhold

Matthew W Peters

Mike M Y Chen

Kai-Dong Zhang

John R Frost

Francesca C Vitali

Hanan Alwaseem

Simone Giovani

Kaidong Zhang

Jessica M Smith

Methods and compositions are provided for the display of genetically encoded macrocyclic peptides on a biological surface. Also provided are nucleic acid molecules, polypeptides, and methods for generating combinatorial libraries of macrocyclic peptides displayed on a biological surface. These methods can be used to produce and screen vast libraries of conformationally constrained peptides in a high-throughput manner, from which macrocyclic peptides with a desired property can be selected and identified.

Methods and compositions for display of macrocyclic peptides

This invention relates to modified hydroxylases. The invention further relates to cells expressing such modified hydroxylases and methods of producing hydroxylated alkanes by contacting a suitable substrate with such cells.

Alkane oxidation by modified hydroxylases

The present invention relates to derivatives of the sesquiterpene lactone micheliolide, methods and compositions for their preparation, and methods for using the micheliolide derivatives in pharmaceutical compositions as anticancer and anti-inflammatory agents. The invention also relates to methods for producing micheliolide derivatives modified at positions C2 and C14. The invention also relates to methods for producing parthenolide derivatives modified at positions C2 and C14 in conjunction with modifications at position C13, via chemoenzymatic methods. The invention further relates to methods for using parthenolide derivatives for treating cancer and inflammatory diseases.

Micheliolide derivatives, methods for their preparation and their use as anticancer and antiinflammatory agents

Derivatives of the antimalarial agent artemisinin, compositions comprising the derivatives, methods for preparing the derivatives, and their uses in pharmaceutical compositions intended for the treatment of parasitic infections are provided. Methods are provided for the production of artemisinin derivatives via functionalization of positions C7 and C6a, and optionally, in conjunction with modifications at positions C10 and C9, via chemoenzymatic methods. Recombinant cytochrome P450 polypeptides are also provided for use in the methods. The artemisinin derivatives can be used for the treatment of malaria and other parasitic infections, alone or in combination with other antiparasitic drugs.

Artemisinin derivatives, methods for their preparation and their use as antimalarial agents

Methods and compositions are provided for generating macrocyclic peptides from genetically encoded, ribosomally produced polypeptide precursors. Also provided are nucleic acid molecules, polypeptides, and methods for generating combinatorial libraries of macrocyclic peptides. These methods can be used to produce vast libraries of conformationally constrained peptide ligands as well as facilitate the functional screening of these libraries to identify compound(s) with desired activity properties.

Methods and compositions for ribosomal synthesis of macrocyclic peptides

Methods and compositions are provided for generating macrocyclic peptides constrained by side-chain-to-C-terminus non-peptidic tethers for use as functional and structural mimics of &#x3b1;-helical motifs, including in therapeutic applications. These methods can be used to produce libraries of conformationally constrained peptidomimetics to identify compounds with desired activity properties.

Macrocyclic peptidomimetics for alpha-helix mimicry

Methods and compositions are provided for covalently linking a chemical species to a recombinant or synthetic polypeptide. The methods involve the reaction of a thioester-comprising polypeptide with a reagent comprising a reactive amino-thiol group connected to the chemical species which is to be covalently linked to the polypeptide, via a linker. Such chemical species can be a functional group, a label or tag molecule, a biological molecule, a ligand, or a solid support. Efficient and catalyst-free methods for C-terminal protein labeling are also provided. The methods expand current capabilities in the area of protein functionalization, providing useful and complementary tools for the isolation, detection, characterization, and analysis of proteins in a variety of in vitro and in vivo applications.

Methods and compositions for site-specific labeling of peptides and proteins

Methods and systems for evaluating and predicting the reactivity of natural and engineered monooxygenase enzymes are provided. Methods are provided for acquiring a functional profile (fingerprint) of monooxygenases that encode information regarding the active site configuration of such monooxygenases. Methods are also provided for carrying out analysis of a monooxygenase fingerprint, to formulate predictions regarding the reactivity properties (e.g., substrate reactivity, chemo-, regio, and stereoselectivity properties) of the fingerprinted monooxygenases.

Methods and systems for evaluating and predicting the reactivity of monooxygenase enzymes

Methods and compositions are provided that utilize synthetic molecules and genetically encoded polypeptides to generate macrocyclic peptide-containing molecules with a hybrid peptidic/non-peptidic backbone. Also provided are nucleic acid molecules, polypeptides, and methods for generating libraries of macrocyclic peptide-containing molecules with a hybrid peptidic/non-peptidic backbone. These methods can be used to increase the structural diversity of ligand libraries as well as facilitate the functional screening of these libraries to identify compound(s) with desired activity properties.

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Rochester, NY, United States of America

Rudi Fasan