Method for producing inhibitors and inhibitors formed therefrom
AssigneeThe University of Akron
InventorsWeiping ZHENG, David George FATKINS
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Abstract
The present invention relates to methods for producing inhibitors for protein deacetylases, and to the compounds and/or products produced by such methods. More specifically, the present invention relates to methods for producing inhibitors for human class III protein deacetylases or sirtuins, and to the compounds and/or products produced by such methods. The present invention provides the transformation of peptide substrates to potent peptide inhibitors by replacement of Nε-thioacetyl-lysine for Nε-acetyl-lysine.
Claims14
A method for transforming a peptide substrate into a selective peptide inhibitor comprising:
- a) providing a peptide substrate containing Nε-acetyl-lysine;
- b) providing an L-Nα-Fmoc-Nε-thioacetyl-lysine building block;
- and
- c) reacting the building block to replace Nε-acetyl-lysine in the peptide substrate with Nε-thioacetyl-lysine from the building block, wherein the resulting peptide exhibits selective inhibition for enzyme activity.
A method for producing inhibitors for human class III protein deacetylases comprising:
- a) providing a peptide substrate containing Nε-acetyl-lysine;
- b) providing an L-Nα-Fmoc-Nε-thioacetyl-lysine building block;
- and
- c) reacting the building block to replace Nε-acetyl-lysine in the peptide substrate with Nε-thioacetyl-lysine from the building block, wherein the resulting peptide exhibits selective inhibition for class III protein deacetylase enzymes.
A peptide-based human sirtuin inhibitor comprising an NE-thioacetyl-lysine-containing peptide-based human sirtuin exhibiting resistance to classical HDAC-enzyme dethioacetylation.
The peptide of claim 12 wherein the peptide exhibits a sequence selected from the group consisting of H2N-KKGQSTSRHK(ThAcK)LMFKTEG-COOH;
- H2N-KKGQSTSRHK(AcK)LMFKTEG-COOH;
- H2N-KKGQSTSRHK(K)LM FKTEG-COOH;
- H2N-MPSD(ThAcK)TIGG-COOH;
- H2N-KRLPKTRSG(ThAcK)VMRRLLRKII-COOH;
- H2N-KRLPKTRSG(AcK)VMRRLLRKII-COOH;
- H2N-KRLPKTRSG(K)VMRRLLRKII-COOH;
- and H2N-HK(ThAcK)LM-COOH.
Dependencies are inferred from the claim text.