Peptidomimetic macrocycles
AssigneeAileron Therapeutics, Inc.
InventorsHuw M. Nash, David Allen Annis, Rosana Kapeller-Llbermann, Tomi K. Sawyer, Noriyuki Kawahata
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Abstract
Biologically active crosslinked polypeptides with improved properties relative to their corresponding precursor polypeptides, having good cell penetration properties and reduced binding to human proteins, and methods of identifying and making such improved polypeptides are described.
Claims25
A method of screening for an enhanced alpha-helical polypeptide with enhanced cellular efficacy in human whole blood, the enhanced alpha-helical polypeptide comprising a cross-linker connecting a first amino acid and a second amino acid of the polypeptide, the method comprising:
- (a) providing a sequence of a parent polypeptide comprising a cross-linker connecting a first amino acid and a second amino acid of the parent polypeptide sequence,
- (b) producing a modified alpha-helical polypeptide having the same sequence as the parent polypeptide sequence except that at least one amino acid side chain that is not essential for target binding is different in comparison to the alpha-helical parent polypeptide sequence, wherein the modified alpha-helical polypeptide comprises a cross-linker connecting a first amino acid and a second amino acid of the modified alpha-helical polypeptide;
- (c) measuring an in vitro activity (EC50) of the modified alpha-helical polypeptide in a whole cell assay wherein activity is mediated by binding to a target, in the presence and absence of human serum;
- (d) determining an apparent affinity (Kd*) of the modified alpha-helical polypeptide for human serum proteins;
- and
- (e) selecting the modified alpha-helical polypeptide as an enhanced alpha-helical polypeptide if the modified alpha-helical polypeptide has a Kd* between about 1 and 700 micromolar.
Dependencies are inferred from the claim text.