Stabilized compounds having secondary structure motifs
First Claim
1. A method for synthesizing a peptide comprising a cross-link, the method comprising:
- (a) synthesizing an amino acid sequence, wherein the amino acid sequence comprises a first amino acid comprising a first moiety and a second amino acid comprising a second moiety, and wherein the first and second moieties are reactive toward one another in the presence of a catalyst; and
(b) reacting the amino acid sequence under conditions sufficient to promote a reaction between the first and second moieties toward each other in the presence of the catalyst, thereby resulting in formation of the cross-link in the peptide;
wherein the cross-link spans one or two turns of an α
-helix;
the cross-link comprises a carbon-carbon double bond; and
the peptide disrupts binding of p53 to MDM2.
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Abstract
The present invention provides novel stabilized crosslinked compounds having secondary structure motifs, libraries of these novel compounds, and methods for the synthesis of these compounds libraries thereof. The synthesis of these novel stabilized compounds involves (1) synthesizing a peptide from a selected number of natural or non-natural amino acids, wherein the peptide comprises at least two moieties capable of undergoing reaction to promote carbon-carbon bond formation; and (2) contacting the peptide with a reagent to generate at least one crosslinker and to effect stabilization of a secondary structure motif. The present invention, in a preferred embodiment, provides stabilized p53 donor helical peptides. Additionally, the present invention provides methods for disrupting the p53/MDM2 binding interaction comprising (1) providing a crosslinked stabilized α-helical structure; and (2) contacting the crosslinked stabilized α-helical structure with MDM2.
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Citations
15 Claims
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1. A method for synthesizing a peptide comprising a cross-link, the method comprising:
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(a) synthesizing an amino acid sequence, wherein the amino acid sequence comprises a first amino acid comprising a first moiety and a second amino acid comprising a second moiety, and wherein the first and second moieties are reactive toward one another in the presence of a catalyst; and (b) reacting the amino acid sequence under conditions sufficient to promote a reaction between the first and second moieties toward each other in the presence of the catalyst, thereby resulting in formation of the cross-link in the peptide; wherein the cross-link spans one or two turns of an α
-helix;
the cross-link comprises a carbon-carbon double bond; and
the peptide disrupts binding of p53 to MDM2. - View Dependent Claims (2, 3, 4, 5, 6, 7, 14, 15)
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8. A method for synthesizing a library of stabilized α
- -helix peptides, the method comprising;
(a) providing a collection of resin-bound amino acids; (b) deprotecting each of said resin-bound amino acids; (c) separating said collection of deprotected resin-bound amino acids into N equal portions, wherein N represents the number of different types of reacting amino acids to be coupled; (d) coupling of each N types of reacting amino acids to each portion of the deprotected resin-bound amino acids; (e) combining each of the N portions together; (f) repeating steps (b)-(e) until a desired peptide product is obtained,
1) wherein at least two of the amino acids within the desired peptide product comprise substituted or unsubstituted vinyl side chains capable of undergoing ring closing metathesis reaction to generate a first cross-linker, or
2) wherein a first amino acid within the desired peptide product comprises a substituted or unsubstituted divinyl side chain, and wherein a second and a third amino acid within the desired peptide comprise substituted or unsubstituted olefins, whereby said divinyl side chain and said olefins are reactive in ring closing metathesis reactions to generate a second and a third cross-linker originating from the first amino acid; and(g) contacting said desired peptide product with a ring closing metathesis catalyst to generate a library of cross-linked stabilized α
-helix peptide structures. - View Dependent Claims (9, 10, 11, 12, 13)
- -helix peptides, the method comprising;
Specification