Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10030049-B2
Publication Date
2018-07-24
Expiration Date
Abstract
The present invention provides novel peptidomimetic macrocycles and methods for their preparation and use, as well as amino acid analogs and macrocycle-forming linkers, and kits useful in their production.
Core Innovation
The invention relates to peptidomimetic macrocycles comprising an alkyne moiety and an amino acid sequence segment comprising an amino acid moiety arranged to comprise an α-helix. The macrocycle-forming linker and variable substituent definitions support formation of a macrocycle with defined geometric constraints related to α-helix turns and ring size, and the compound comprises an α-helix.
The disclosed macrocycles are described as stabilizing an α-helical structure in solution, including embodiments that enable intrahelical hydrogen bonding when a defined substituent variable is H. The linkers are selected to stabilize desired secondary structure, with linker span across α-helix turns and resultant ring size described in terms of members on the order of about 17-82.
The document also describes peptidomimetic macrocycles derived from secondary-structure peptide ligands, including BCL-2 family BH3 domains such as BID, BIM, BAD, and PUMA, a p53/MDM2 binding region, BH3-site peptides, and GPCR ligand peptides. It further discloses modifications such as lipidation and PEGylation to facilitate cellular uptake and improved biological properties, and describes azide-alkyne macrocyclization to generate triazole-linked macrocycles using macrocyclization reagents.
Claims Coverage
The provided independent claims center on a peptidomimetic macrocycle compound with an alkyne moiety and an amino acid sequence segment configured to comprise an α-helix, with extensive structural substituent definitions. In total, the claims content explicitly presents 2 inventive features.
Peptidomimetic macrocycle with alkyne moiety and α-helix amino acid sequence
A compound comprising a peptidomimetic macrocycle, an alkyne moiety, and an amino acid sequence comprising an amino acid moiety, wherein the compound comprises an α-helix.
α-helix-configured amino acid substituent scope
The amino acid sequence includes multiple variable substituent and protecting-group options, with defined integer ranges for g, h, and n, configured so that the overall compound comprises an α-helix.
Overall, the claims coverage centers on peptidomimetic macrocycle compounds that incorporate an alkyne moiety and an amino acid sequence segment arranged to comprise an α-helix, with broadly permissive chemical substituent definitions for multiple structural variables.
Stated Advantages
Increased helical structure in aqueous solution relative to a corresponding non-macrocyclic polypeptide.
Increased thermal stability relative to a corresponding non-macrocyclic polypeptide.
Increased biological activity.
Increased resistance to proteolytic degradation relative to a corresponding non-macrocyclic polypeptide.
Increased cell penetration.
Facilitated cellular uptake, including improved bioavailability and blood circulation.
Increased target affinity compared with non-macrocyclic polypeptides.
Increased structural stability compared with non-macrocyclic polypeptides.
Documented Applications
Assay context for BH3/BCL-X_L system.
Assay context for p53/MDM2 system.
In vivo stability is referenced in the assay context.
Target peptide sequence examples and peptide ligands are provided, including peptides derived from BCL-2 family BH3 domains, a p53/MDM2 binding region, BH3-site peptides, and GPCR ligand peptides, with cross-linked variants.
Peptidomimetic macrocycles are described with modifications intended to improve biological properties and facilitate cellular uptake.
Interested in licensing this patent?