| 摘要 |
1. An inhibitory peptide capable of inhibiting beta pleated sheet formation in amyloid beta-peptide said inhibitory peptide wherein a peptide analog is a 5 residue Alzheimer inhibitor peptide iAbeta5 (SEQ ID NO:1 Leu-Pro-Phe-Phe-Asp) designed by chemical modification and achieved by a process selected from the group consisting of: alteration of the N-and C-terminal ends of said Alzheimer inhibitor peptide iAbeta5; replacing at least one residue of said Alzheimer inhibitor peptide iAbeta with alpha-aminoisobuiric acid (Aib); methylation of the alpha carbon of at least one residue of said Alzheimer inhibitor peptide iAbeta5; replacing at least one L-enantiomeric residue of said Alzheimer inhibitor peptide iAbeta5 with a D-enantiomeric residue, forming head to tail cyclization of said Alzheimer inhibitor peptide iAbeta5, replacing amide bonds in said Alzheimer inhibitor peptide iAbeta5 with an amide bond surrogate; and combinations thereof. 2. The inhibitory peptide of claim 1 wherein said alteration of the N-and C-terminal ends of said Alzheimer inhibitor peptide iAbeta5 is achieved by a process selected from acetylation, amidation, desamination, alcoholization and combinations thereof. 3. The inhibitory peptide of claim 2 wherein said inhibitory peptide is selected from the group consisting of: 4. The inhibitory peptide of claim 2 wherein said inhibitory peptide is ac-Leu Pro Phe Phe Asp-am. 5. The inhibitory peptide of claim 1 wherein said inhibitory peptide is selected from the group consisting of: 6. The inhibitory peptide of claim 3 wherein said inhibitory peptide is characterized by the following structure: 7. An inhibitory peptide capable of inhibiting conformational changes in prion PrP protein associated with amyloidosis which is an analog of 13 residue prion inhibitor peptide iPrP13 (SEQ ID NO: 2 Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val) designed by chemical modification SEQ ID NO :2, said chemical modification is achieved by a process selected from the group consisting of: alteration of the N-and C-terminal ends of said prion inhibitor peptide iPrP13; replacing at least one residue of said prion inhibitor peptide iPrP13 with alpha-aminoisobuiric acid (Aib); methylation of the alpha carbon of at least one residue of said prion inhibitor peptide iPrP13; replacing at least one L-enantiomeric residue of said prion inhibitor peptide iPrP13 with a D-enantiomeric residue, forming head to tail cyclization of said prion inhibitor peptide iPrP13, replacing amide bonds in said prion inhibitor peptide iPrP13 with an amide bond surrogate; and combinations thereof. 8. The inhibitory peptide of claim 7 wherein said alteration of the N-and C-terminal ends of said prion inhibitor peptide iPrP13 is achieved by a process selected from acetylation, amidation, desamination, alcoholization and combinations thereof. 9. The inhibitory peptide of claim 2 wherein said inhibitory peptide is selected from the group consisting of: 10. The inhibitory peptide of claim 2 wherein said inhibitory peptide is selected from the group consisting of: 11. The inhibitory peptide of claim 3 wherein said inhibitory peptide is characterized by the following structure: 12. A method for reducing the formation of amyloid or amyloid like deposits involving abnormal folding into beta sheet structure of amyloid beta peptide or for reducing the amount of said amyloid beta peptide which has already formed into a beta sheet structure comprising bringing into the presence of said amyloid beta peptide either prior to or after the abnormal folding thereof into a beta sheet structure, an effective amount of the peptide of claim 1. 13. A method for reducing the formation of amyloid or amyloid like deposits involving conformational changes in prion Pr protein or reducing the amount of said prion Pr protein which has already formed into amyloid or amyloid-like deposits comprising bringing into the presence of said prion Pr protein either prior to or after said conformational changes thereof into amyloid deposits an effective amount of the peptide of claim 7. 14. A method for reducing the formation of amyloid or amyloid like deposits by administration of a peptide selected from one of the group consisting of: 15. A pharmaceutical composition, comprising an inhibitory peptide capable of inhibiting beta pleated sheet formation in amyloid beta-peptide and a pharmaceutically acceptable carrier or excipient, said inhibitory peptide analog is a 5 residue Alzheimer inhibitor peptide iAbeta5 (SEQ ID NO: 1 Leu-Pro-Phe-Phe-Asp) designed by chemical modification and achieved by a process selected from the group consisting of: alteration of the N-and C-terminal ends of said Alzheimer inhibitor peptide iAbeta5; replacing at least one residue of said Alzheimer inhibitor peptide iAbeta with alpha-aminoisobuiric acid (Aib); methylation of the alpha carbon of at least one residue of said Alzheimer inhibitor peptide iAbeta5; replacing at least one L-enantiomeric residue of said Alzheimer inhibitor peptide iAbeta5 with a D-enantiomeric residue, forming head to tail cyclization of said Alzheimer inhibitor peptide iAbeta5, replacing amide bonds in said Alzheimer inhibitor peptide iAbeta5 with an amide bond surrogate; and combinations thereof. 16. The pharmaceutical composition of claim 15 wherein said inhibitory peptide is selected from the group consisting of: 17. The pharmaceutical composition of claim 15 wherein said inhibitory peptide is ac-Leu Pro Phe Phe Asp-am. 18. The pharmaceutical composition of claim 15 19. The pharmaceutical composition of claim 15 wherein said inhibitory peptide peptide is characterized by the following structure: 20. A pharmaceutical composition, comprising an inhibitory peptide inhibiting conformational changes in prion PrP protein associated with amyloidosis which is an analog of 13 residue prion inhibitor peptide iPrP13 (SEQ ID NO: 2 Asp Ala Pro Ala Ala Pro Ala Gly Pro Ala Val Pro Val) designed by chemical modification SEQ ID NO: 2, said chemical modification is achieved by a process selected from the group consisting of: alteration of the N-and C-terminal ends of said prion inhibitor peptide iPrP13; replacing at least one residue of said prion inhibitor peptide iPrP13 with alpha-aminoisobuiric acid (Aib); methylation of the alpha carbon of at least one residue of said prion inhibitor peptide iPrP13; replacing at least one L-enantiomeric residue of said prion inhibitor peptide iPrP13 with a D-enantiomeric residue, forming head to tail cyclization of said prion inhibitor peptide iPrP13, replacing amide bonds in said prion inhibitor peptide iPrP13 with an amide bond surrogate; and combinations thereof. 21. The pharmaceutical composition of claim 20 wherein said inhibitory peptide is selected from the group consisting of: 22. The pharmaceutical composition of claim 20 wherein said inhibitory peptide is selected from the group consisting of: 23. The pharmaceutical composition of claim 20 wherein said inhibitory peptide is characterized by the following structure:
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