Methods for preparing purified polypeptide compositions
Inventors
Nash, Huw M. • Iadanza, Matthew • Leitheiser, Christopher • Kawahata, Noriyuki
Assignees
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Publication Number
US-9206223-B2
Publication Date
2015-12-08
Expiration Date
Abstract
The present invention relates to purified peptidomimetic macrocycles. The invention additionally provides methods of preparing and using such macrocycles, for example in therapeutic applications.
Core Innovation
The invention concerns methods for preparing a pharmaceutical composition that includes a purified peptidomimetic macrocycle comprising an alpha-helix. A peptidomimetic precursor attached to a solid support is contacted with a metathesis catalyst comprising a metal, or ruthenium, to produce a crude peptidomimetic macrocycle comprising a cross-linker connecting a first amino acid and a second amino acid, wherein the cross-linker spans from 1 turn to 5 turns of the alpha-helix.
After metathesis, the crude peptidomimetic macrocycle is purified to provide a purified peptidomimetic macrocycle composition containing less than 10 ppm by weight of the metal from the metathesis catalyst, including less than 10 ppm by weight of ruthenium where the catalyst is ruthenium. The purifying comprises washing the crude peptidomimetic macrocycle with a solvent prior to removing the crude peptidomimetic macrocycle from the solid support, to reduce residual metal from the catalyst.
The purified peptidomimetic macrocycle composition is then formulated into a pharmaceutical composition for administration to a human subject. The document further frames peptidomimetic macrocycles as part of therapeutic use cases targeting BCL-2 family mediated disorders and p53/MDM2 antagonism.
Claims Coverage
The independent claims cover a method for preparing and formulating a pharmaceutical composition comprising a purified peptidomimetic macrocycle with an alpha-helix, produced by metathesis of a solid-supported peptidomimetic precursor, followed by purification to control catalyst metal impurity levels and solvent washing prior to solid-support removal. Across the independent claims, the coverage centers on four inventive features.
Solid-supported metathesis to form an alpha-helical cross-linked peptidomimetic macrocycle
Contacting a peptidomimetic precursor attached to a solid support comprising at least two moieties capable of undergoing a metathesis reaction with a metathesis catalyst comprising a metal or ruthenium to produce a crude peptidomimetic macrocycle comprising a cross-linker connecting a first amino acid and a second amino acid, wherein the cross-linker spans from 1 turn to 5 turns of the alpha-helix.
Purification by solvent washing to reduce catalyst metal impurities below 10 ppm
Purifying the crude peptidomimetic macrocycle to result in a purified peptidomimetic macrocycle composition comprising less than 10 ppm by weight of the metal from the metathesis catalyst, wherein the purifying comprises washing the crude peptidomimetic macrocycle with a solvent prior to removing the crude peptidomimetic macrocycle from the solid support.
Formulation into a pharmaceutical composition for human administration
Formulating the purified peptidomimetic macrocycle composition into the pharmaceutical composition for administration to a human subject.
Ruthenium metathesis with ruthenium residue control below 10 ppm
Contacting a peptidomimetic precursor attached to a solid support comprising at least two moieties capable of undergoing a metathesis reaction with a metathesis catalyst comprising ruthenium to produce a crude peptidomimetic macrocycle comprising a cross-linker connecting a first amino acid and a second amino acid, wherein the cross-linker spans from 1 turn to 5 turns of the alpha-helix; purifying to result in a purified peptidomimetic macrocycle composition comprising less than 10 ppm by weight of ruthenium from the metathesis catalyst; wherein the purifying comprises washing with a solvent prior to removing from the solid support.
The claim set emphasizes preparing an alpha-helical peptidomimetic macrocycle by metathesis of a solid-supported precursor, using catalyst metal including ruthenium to form an amino-acid cross-linker spanning 1–5 alpha-helix turns, and purifying by solvent washing to achieve a purified macrocycle composition with less than 10 ppm metal or less than 10 ppm ruthenium. The method concludes with formulation into a pharmaceutical composition for administration to a human subject.
Stated Advantages
Purification results in a purified peptidomimetic macrocycle composition comprising less than 10 ppm by weight of the metal from the metathesis catalyst.
Purification results in a purified peptidomimetic macrocycle composition comprising less than 10 ppm by weight of ruthenium from the metathesis catalyst.
Dependent limitations further reduce catalyst residues to less than 1 ppm by weight of the metal or ruthenium, where specified.
Documented Applications
Administration to a human subject as a pharmaceutical composition.
Therapeutic use targeting BCL-2 family mediated disorders.
Therapeutic use for p53/MDM2 antagonism.
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