Amyloid-beta peptide crystal structure

Abstract

The invention relates provides a novel crystal structure of the fibrillogenic part of amyloid β-peptide (Aβ). More specifically the crystal structure is Aβ-IgNAR and, accordingly the present invention also relates to selecting and/or designing compounds that modulate amyloid β-peptide (Aβ) activity using techniques such as in silico screening and crystal soaking experiments. The invention further relates to compounds and methods for inhibiting interaction between amyloid β-peptide (Aβ) monomers, more particularly, inhibiting or disrupting amyloid β-peptide (Aβ) oligomer formation and toxic activity.

1 - 23 . (canceled) 
     
     
         24 . A compound for inhibiting, disrupting or detecting amyloid β-peptide oligomer formation or toxic activity, wherein the compound interacts with one or more amino acids 18-41 of the Ap protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         25 . A compound as claimed in  claim 24  wherein the compound interacts with the region of Aβ-peptide defined by N27, K28, I32 and L34 of Aβ-peptide wherein amino acids 18-41 of the Aβ protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         26 . A compound as claimed in  claim 24  wherein the compound interacts with the region of Aβ-peptide defined by F19, A21, G25, N27, K28, G29, I31, L34 of Aβ-peptide wherein amino acids 18-41 of the Aβ protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         27 . A compound as claimed in  claim 25  in which the compound is the peptide 27-NKGAI-31 to compete with formation of the dimer. 
     
     
         28 . A compound as claimed in  claim 25  in which the compound is the peptide 27-NKxxIxxL-34 (wherein x is any amino acid). 
     
     
         29 . A compound as claimed in  claim 24  in which the compound is an antibody or an antigen binding region thereof which binds Aβ-peptide in the region defined by N2′7, K28, I31 and L34. 
     
     
         30 . A compound as claimed in  claim 24  in which the compound is an antibody or an antigen binding region thereof which binds Ap-peptide in the region defined by F19, A21, G25, N27, K28, G29, I31, L34. 
     
     
         31 . A compound as claimed in  claim 24  wherein the compound interacts with the region of Aβ-peptide defined by G33, L34, M35 and V36 of Aβ-peptide wherein amino acids 18-41 of the Aβ protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         32 . A compound as claimed in  claim 24  wherein the compound interacts with the region of Aβ-peptide defined by I32, G33, L34, M35, V36 of Aβ-peptide wherein amino acids 18-41 of the Aβ protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         33 . A compound as claimed in  claim 31  in which the compound is the peptide 33-GLMV-36 to compete for tetramer with or without flanking residues, 
     
     
         34 . A compound as claimed in  claim 31  in which the compound is the peptide 31-IIGLxV-36 (wherein x is any amino acid). 
     
     
         35 . A compound as claimed in  claim 31  in which the compound is an antibody or an antigen binding region thereof which binds Ap-peptide in the region defined by G33, L34, M35 and V36. 
     
     
         36 . A compound as claimed in  claim 32  in which the compound is an antibody or an antigen binding region thereof which binds Aβ-peptide in the region defined by I32, G33, L34, M35, V36. 
     
     
         37 . A compound as claimed in  claim 24  wherein the compound interacts with the region of Ap-peptide defined by V18, F20, S26, K28, G29, I32, M35, V39 and I41 of Aβ-peptide wherein amino acids 18-41 of the Ap protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         38 . A compound as claimed in  claim 24  wherein the compound interacts with the region of Aβ-peptide defined by V18, F20, D23, S26, K28, A30, I32, M35, G37, V39, I41 of Aβ-peptide wherein amino acids 18-41 of the Aβ protein are positioned at atomic coordinates as shown in Appendix I, or structural coordinates having a root mean square deviation from the backbone atoms of said amino acids of not more than 1.5 Å. 
     
     
         39 . A compound as claimed in  claim 37  in which the compound is the peptide selected from the group consisting of the peptides 26-SxKG-29, 18-VxF-20, 32-IxxM-35, and 39-VxI-41 each with or without flanking sequences; wherein the peptide competes for formation of amyloid. 
     
     
         40 . A compound as claimed in  claim 37  in which the compound is an antibody or an antigen binding region thereof which binds Aβ-peptide in the region defined by V18, F20, S26, K28, G29, I32, M35, V39 and I41. 
     
     
         41 . A compound as claimed in  claim 38  in which the compound is an antibody or an antigen binding region thereof which binds A) 3 -peptide in the region defined by V18, F20, D23, S26, K28, A30, I32, M35, G37, V39 and I41. 
     
     
         42 - 49 . (canceled)