Wisconsin Alumni Research Foundation

Longevity Biotech, Inc.

Leland Stanford Junior University

Northwestern University

Harvard College

The General Hospital Corporation

Uchicago Argonne, LLC

Samuel Helmer Gellman

Shannon S Stahl

Pil Seok Chae

Bernard Weisblum

Li Guo

Scott Shandler

Denis Kissounko

Sarah Elizabeth Lee

Lisa M Johnson

Mehmet F Ilker

Brian K Kobilka

Xifang Wang

William Seth Horne

Annelise E Barron

Michael A Gelman

Michelle Dohm

Soren Rasmussen

John M Gledhill

Daniel H Appella

Brendan P Mowery

Yonggui Chi

Bayard R Huck

Michael Giuliano

William C Pomerantz

David M Lynn

Thomas J Gardella

Alan D Attie

Alan Saghatelian

Mark Patrick Keller

Daniel Alan Klein

Marc J Wander

Ahlke Hayen

Emilie Porter

Margaret A Schmitt

Matthew Woll

Felix N Ngassa

Laurie A Christianson

Yong Jun Chung

Nicholas Lawrence Abbott

David B Rozema

Ronald Thaddeus Raines

Sean Paul Palecek

Philip D Laible

Naoki Umezawa

Ross W Cheloha

Phillip D Laible

Shonna M McBride

Hee-Seung Lee

Paul LePlae

Christen Bell Smith

Emily P English

Sarah E Eldred

Jonathan R Lai

Justin Murray

Terra Potocky

Soren Rasumssen

Michele R Richards

James W Checco

Susanne Krauth&auml;user

Amy J Karlsson

D Tyler McQuade

Susanne Krauthauser

Runhui Liu

Shi Liu

Scott J Shandler

Firat Ilker

Described are polypeptide analogs of parathyroid hormone (PTH) that include an unnatural amino acid substitution at positions 7 or 8 from the N-terminus of the polypeptide. Also described are pharmaceutical compositions useful for treating hypoparathyroidism that contain the analogs and methods of using the analogs to treat hypoparathyroidism.

Analogues of parathyroid hormone (1-34) that function as agonists of the parathyroid hormone receptor-1 and display modified activity profiles

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an &#x3b1;-amino acid and at least one &#x3b2;-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.

Peptides comprising non-natural amino acids and methods of making and using the same

Highly active polypeptides and methods of making and using the same

Non-natural oligomers have recently shown promise as functional analogues of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Presented herein an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of &#x3b2;-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers affords further improvements by reducing the percent surface area compression to reach low minimum surface tension.

Nylon-3 co-polymers and synthetic lung surfactant compositions containing same

Described herein are peptide analogs of glucagon-like peptide 1 (GLP-1) that retain agonist activity, but are more resistant to proteolytic degradation than native GLP-1. In the analogs, at least one &#x3b1;-amino acid found in the native GLP-1 is replaced with a &#x3b2;-amino acid residue, which may or may not be cyclically constrained. Pharmaceutical compositions containing the analogs are described, as are methods to treat diabetes, and methods to make proteolytically resistant GLP-1 analogs.

Alpha/beta-polypeptide analogs of glucagon-like peptide 1

Described is a method of fabricating biologically active, unnatural polypeptides. The method includes the steps of selecting a biologically active polypeptide or biologically active fragment thereof having an amino acid sequence comprising &#x3b1;-amino acid residues, and fabricating a synthetic polypeptide that has an amino acid sequence that corresponds to the sequence of the biologically active polypeptide, but wherein about 14% to about 50% of the &#x3b1;-amino acid residues found in the biologically active polypeptide or fragment of step (a) are replaced with &#x3b2;-amino acid residues, and the &#x3b1;-amino acid residues are distributed in a repeating pattern.

Method of making biologically active alpha-beta peptides

Described are polypeptide analogs of parathyroid hormone (PTH) that include at least two non-adjacent &#x3b2;-amino acid residues in place of a naturally occurring &#x3b1;-amino acid residues. Also described are pharmaceutical compositions useful for treating hypoparathyroidism that contain the analogs and methods of using the analogs to treat hypoparathyroidism.

Alpha-/beta-polypeptide analogs of parathyroid hormone (PTH) and method of using same

A method and corresponding composition to inhibit outgrowth ofspores and/or to inhibit growth ofvegetative cells in a mammal in which an amount of a nylon-3 polymer or nylon-3 copolymer or a pharmaceutically suitable salt thereof is administered to the subject.

Nylon-3 polymers active against

Disclosed are isolated, unnatural polypeptides containing cyclically-constrained &#x3b2;-amino acid residues and cyclically-constrained &#x3b3;-amino acid residues. The compounds are unnatural and because they contain rotationally constrained residues that are not amenable to enzymatic degradation, the compounds are useful to probe protein-protein and other large molecule interactions.

Heterogeneous foldamers containing &#x3b1;, &#x3b2;, and/or &#x3b3;-amino acids

Disclosed is a method of making &#x3b2;-polypeptides. The method includes polymerizing &#x3b2;-lactam-containing monomers in the presence of a base initiator and a co-initiator which is not a metal-containing molecule to yield the product &#x3b2;-polypeptides. Specifically disclosed are methods wherein the base initiator is potassium t-butoxide, lithium bis(trimethylsilyl)amide (LiN(TMS)), potassium bis(trimethyl-silyl)amide, and sodium ethoxide, and the reaction is carried out in a solvent such as chloroform, dichloromethane, dimethylsulfoxide, or tetrahydrofuran.

Poly-&#x3b2;-peptides from functionalized &#x3b2;-lactam monomers and antibacterial compositions containing same

The invention provides tandem facial amphiphiles for biochemical manipulations and characterization of membrane proteins, such as intrinsic membrane proteins. Members of this new family display favorable behavior with several membrane proteins. These amphiphiles can form relatively small micelles, and small changes in amphiphile chemical structures can result in large changes in their physical properties. The tandem facial amphiphiles can be used to aid the solubilization, isolation, purification, stabilization, crystallization, and/or structural determination of membrane proteins.

Tandem facial amphiphiles

Non-natural oligomers have recently shown promise as functional analogs of lung surfactant proteins B and C (SP-B and SP-C), two helical and amphiphilic proteins that are critical for normal respiration. The generation of non-natural mimics of SP-B and SP-C has previously been restricted to step-by-step, sequence-specific synthesis, which results in discrete oligomers that are intended to manifest specific structural attributes. Presented herein an alternative approach to SP-B mimicry that is based on sequence-random copolymers containing cationic and lipophilic subunits. These materials, members of the nylon-3 family, are prepared by ring-opening polymerization of &#x3b2;-lactams. The best of the nylon-3 polymers display promising in vitro surfactant activities in a mixed lipid film. Pulsating bubble surfactometry data indicate that films containing the most surface-active polymers attain adsorptive and dynamic-cycling properties that surpass those of discrete peptides intended to mimic SP-B. Attachment of an N-terminal octadecanoyl unit to the nylon-3 copolymers affords further improvements by reducing the percent surface area compression to reach low minimum surface tension.

The invention provides compounds and methods, for example, to carry out organocatalytic Michael additions of aldehydes to cyclically constrained nitroethylene compounds catalyzed by a proline derivative to provide cyclically constrained &#x3b1;-substituted-&#x3b3;-nitro-aldehydes. The reaction can be rendered enantioselective when a chiral pyrrolidine catalyst is used, allowing for Michael adducts in nearly optically pure form (e.g., 96 to &#x3e;99% e.e.). The Michael adducts can bear a single substituent or dual substituents adjacent to the carbonyl. The Michael adducts can be efficiently converted to cyclically constrained protected &#x3b3;-amino acid residues, which are essential for systematic conformational studies of &#x3b3;-peptide foldamers. New methods are also provided to prepare other &#x3b3;-amino acids and peptides. These new building blocks can be used to prepare foldamers, such as &#x3b1;/&#x3b3;-peptide foldamers, that adopt specific helical conformations in solution and in the solid state.

Gamma amino acid building blocks

This invention relates to novel compositions comprising analogs of glucagon, wherein the analog comprises an &#x3b1;-amino acid and at least one &#x3b2;-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways, including diabetes and other metabolic disorders. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.

Compositions comprising glucagon analogs and methods of making and using the same

Growing community of inventors

Madison, WI, United States of America

Samuel Helmer Gellman