Harvard College

Fog Pharmaceuticals, Inc.

Agency for Science, Technology and Research

Gerard Hilinski

Gregory Lawrence Verdine

John Hanney McGee

Matthew Reiser Patton

Paula Cristina Ortet

So Youn Shim

Charles William Johannes

Tsz Ying Yuen

Minyun Zhou

Rebecca Yue Liang

Yvonne Alice Nagel

The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups; R, R, R, R, R, R, R, R, R, R, R, L, L, L, L, X, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.

Stapled and stitched polypeptides and uses thereof

Among other things, the present disclosure provides technologies for modulating functions of beta-catenin. In some embodiments, the present disclosure provides stapled peptides that interact with beta-catenin. In some embodiments, provided stapled peptides interact with beta-catenin at an Axin-binding site of beta-catenin. In some embodiments, the present disclosure provides compounds, compositions and methods for preventing and/or treating conditions, disorders and diseases that are associated with beta-catenin.

Agents modulating beta-catenin functions and methods thereof

Described herein is an operationally simple, one-pot solid-supported preparation of saturated stapled peptides. Following completion of ruthenium-catalysed metathesis, solid-phase transfer hydrogenation was achieved using triethylhydrosilane at elevated temperatures. The utility of the method has been demonstrated on 14- and 16-mer peptides to yield the corresponding cyclic a-helix stabilised stapled peptides.

Method of preparing stapled peptides

Provided herein are stabilized &#x3b1;-CT polypeptides comprising an alpha-helical segment, and wherein the polypeptide is of Formula (I-1) or Formula (I-2): R&#x2014;[X]&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;[X]&#x2014;R(I-1) R&#x2014;[X]&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;X&#x2014;[X]&#x2014;R(I-2) wherein the &#x3b1;-CT polypeptide binds to the insulin receptor, and wherein the &#x3b1;-CT polypeptide includes at least one staple (i.e. two cross-linked amino acids) and/or at least one stitch (i.e. three cross-linked amino acids). Further provided are insulin analogs including the stapled or stitched &#x3b1;-CT polypeptides, pharmaceutical compositions thereof, methods of use, e.g., methods of treating a diabetic condition or complications thereof.

Stabilized polypeptide insulin receptor modulators

The present invention provides stapled polypeptides of the Formulae (I) and (VI): (I) (VI) and salts thereof; wherein the groups; R, R, R, R, R, R, R, R, R, R, R, L, L, L, L, X, v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis. 

Growing community of inventors

Somerville, MA, United States of America

Gerard Hilinski