Synthetic beta-amyloid peptides capable of forming stable antigenic oligomers
Synthetic Aβ peptides, oligomers, their methods of synthesis, and their applications are provided. The Aβ peptides can form stable, soluble oligomers important for the advancement of knowledge, detection, and treatment of Alzheimer's disease. Antibodies specific to oligomeric Aβ and their methods of synthesis are also described.
1. A compound comprising:
a synthetic beta-amyloid peptide wherein the synthetic beta-amyloid peptide is a peptide selected from a group consisting of:
a peptide comprising Seq. ID. No. 3 or a substantially similar sequence;
a peptide comprising Seq. ID. No. 4 or a substantially similar sequence;
a peptide consisting of a first and a second strand, wherein the first strand comprises Seq. ID No. 5 or a substantially similar sequence, and the second strand comprises Seq. ID No. 6 or a substantially similar sequence;
wherein the first and second strand are covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the first strand to the C-terminus of the second strand; and
wherein the first and second strand are also covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the second strand to the C-terminus of the first strand; and
a peptide consisting of a first and a second strand, wherein the first strand comprises Seq. ID No. 7 or a substantially similar sequence, and the second strand comprises Seq. ID No. 8 or a substantially similar sequence;
wherein the first and second strand are covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the first strand to the C-terminus of the second strand; and
wherein the first and second strand are also covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the second strand to the C-terminus of the first strand;
wherein any of the substantially similar sequences consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide in its identified position.
2. The compound of claim 1 , wherein any of the substantially similar sequences consists of an addition, a removal, or a substitution of up to two amino acids but still maintains each cysteine amino acid of the peptide in its identified position.
3. The compound of claim 1 , wherein any of the substantially similar sequences consists of an addition, a removal, or a substitution of one amino acids but still maintains each cysteine amino acid of the peptide in its identified position.
4. The compound of claim 1 , wherein any of the sequences is an identical sequence that does not have an addition, a removal, or a substitution of an amino acid.
5. The compound of claim 1 , further comprising at least two more synthetic beta-amyloid peptides, wherein three synthetic beta-amyloid peptides are covalently linked by cysteine disulfide bridges to form a trimer.
6. The compound of claim 5 , wherein the trimer consists of a first, a second, and a third synthetic beta-amyloid peptide;
wherein each peptide consists of a first and a second strand;
wherein the first strand comprises Seq. ID No. 5 or a substantially similar sequence, and the second strand comprises Seq. ID No. 6 or a substantially similar sequence;
wherein the first and second strand are covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the first strand to the C-terminus of the second strand, and
wherein the first and second strand are also covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the second strand to the C-terminus of the first strand;
wherein the cysteine in amino acid position two of the first strand of the first peptide forms a disulfide linkage with the cysteine in amino acid position six of the first strand of the second peptide;
wherein the cysteine in amino acid position two of the first strand of the second peptide forms a disulfide linkage with the cysteine in amino acid position six of the first strand of the third peptide;
wherein the cysteine in amino acid position two of the first strand of the third peptide forms a disulfide linkage with the cysteine in amino acid position six of the first strand of the first peptide; and
wherein any of the substantially similar sequences consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide in its identified position.
7. The compound of claim 5 , wherein the trimer consists of a first, a second, and a third synthetic beta-amyloid peptide;
wherein each consists of a first and a second strand;
wherein the first strand comprises Seq. ID No. 7 or a substantially similar sequence, and the second strand comprises Seq. ID No. 8 or a substantially similar sequence;
wherein the first and second strand are covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the first strand to the C-terminus of the second strand, and
wherein the first and second strand are also covalently linked by the delta-amino group of the side chain of the N-terminal ornithine of the second strand to the C-terminus of the first strand;
wherein the cysteine in amino acid position two of the second strand of the first peptide forms a disulfide linkage with the cysteine in amino acid position six of the second strand of the second peptide;
wherein the cysteine in amino acid position two of the second strand of the second peptide forms a disulfide linkage with the cysteine in amino acid position six of the second strand of the third peptide;
wherein the cysteine in amino acid position two of the second strand of the third peptide forms a disulfide linkage with the cysteine in amino acid position six of the second strand of the first peptide; and
wherein any of the substantially similar sequences consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide in its identified position.
8. The compound of claim 5 , wherein at least one synthetic beta-amyloid peptide incorporates an ornithine in the amino acid position that corresponds to methionine35 of a naturally occurring beta-amyloid peptide.
9. The compound of claim 5 , wherein at least one central amino acid is N-methylated.
10. The compound of claim 5 , wherein the synthetic beta-amyloid peptide has at least one amino acid mutation that corresponds to familial Alzheimer's disease.
11. The compound of claim 5 , wherein the trimer consists of a first, a second, and a third synthetic beta-amyloid peptide;
wherein each peptide comprises Seq. ID No. 3 or a substantially similar sequence;
wherein the cysteine in amino acid position two of the first peptide forms a disulfide linkage with the cysteine in amino acid position six of the second peptide;
wherein the cysteine in amino acid position two of the second peptide forms a disulfide linkage with the cysteine in amino acid position six of the third peptide;
wherein the cysteine in amino acid position two of the third peptide forms a disulfide linkage with the cysteine in amino acid position six of the first peptide; and
wherein the substantially similar sequence consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide in its identified position.
12. The compound of claim 5 , wherein the trimer consists of a first, a second, and a third synthetic beta-amyloid peptide;
wherein each peptide comprises Seq. ID No. 4 or a substantially similar sequence;
wherein the cysteine in amino acid position fifteen of the first peptide forms a disulfide linkage with the cysteine in amino acid position nineteen of the second peptide;
wherein the cysteine in amino acid position fifteen of the second peptide forms a disulfide linkage with the cysteine in amino acid position nineteen of the third peptide;
wherein the cysteine in amino acid position fifteen of the third peptide forms a disulfide linkage with the cysteine in amino acid position nineteen of the first peptide; and
wherein the substantially similar sequence consists of an addition, a removal, or a substitution of up to three amino acids yet maintains each cysteine amino acid of the peptide in its identified position.