WO2015062803A1 - Segments modifiés de polypeptide amyloïde des îlots - Google Patents

Segments modifiés de polypeptide amyloïde des îlots Download PDF

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WO2015062803A1
WO2015062803A1 PCT/EP2014/070989 EP2014070989W WO2015062803A1 WO 2015062803 A1 WO2015062803 A1 WO 2015062803A1 EP 2014070989 W EP2014070989 W EP 2014070989W WO 2015062803 A1 WO2015062803 A1 WO 2015062803A1
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peptide based
based compound
seq
group
iapp
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PCT/EP2014/070989
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Aphrodite KAPURNIOTU
Erika ANDREETTO
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Kapurniotu Aphrodite
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a peptide based compound and its use in a method of prophylactic or therapeutic treatment of at least one amyloidogenic disease or use in a method of non-invasive in vivo and/or in vitro diagnosis of at least one amyloidogenic (protein aggregation) disease.
  • Alzheimer's disease and type 2 Diabetes, also called Diabetes type 2 are two cell degenerative diseases and major representatives of the class of protein aggregation diseases (Westermark P. Aspects on human amyloid forms and their fibril polypeptides. FEBS J. 2005; 272: 5942-9; Dobson CM. Protein aggregation and its consequences for human disease. Protein Pept Lett. 2006; 13: 219-27).
  • amyloid forming polypeptide in Alzheimer's disease is the 40 to 42 residue polypeptide beta-amyloid peptide, also called ⁇ or A- beta. This peptide is present in the blood and cerebrospinal fluid at low nanomolar concentrations and aggregates under conditions of Alzheimer's disease into cell toxic oligomers and amyloid fibrils in the brain. Formation of these cell toxic oligomers and of insoluble amyloid plaques is linked with neurodegeneration and Alzheimer's dis- ease pathogenesis.
  • insoluble amyloid plaques are present in the pancreata of more than 95% of the type 2 Diabetes patients.
  • These amyloid deposits consist mainly of aggregates of the 37- residue islet amyloid polypeptide, abbreviated as IAPP.
  • IAPP is syn- thesized and secreted from the beta-cells of pancreas together with insulin. In its soluble form it acts as a neuroendocrine regulator of glucose homeostasis.
  • formation of IAPP amyloid aggregates in the pancreas is associated with pancreatic ⁇ -cell damage and type 2 Diabetes pathogenesis.
  • Alzheimer's disease has been suggested to be "type 3 diabetes" (O'Nuallain B, Williams AD, Westermark P, Wetzel R. Seeding specificity in amyloid growth induced by heterologous fibrils. J Biol Chem.
  • Alzheimer's disease and type 2 Diabetes appear to be linked also on the molecular level (O'Nuallain B, 2004, above; Yan LM, 2007, above; Miklossy J, above; Andreetto E, Yan LM, Tatarek- Nossol M, et al. Identification of hot regions of the Abeta-IAPP inter- action interface as high-affinity binding sites in both cross- and self- association. Angew Chem Int Ed Engl. 2010; 49: 3081 -5). In fact, ⁇ and IAPP which are both confornnationally flexible but these highly amyloidogenic peptides have a sequence similarity of 25% and a sequence identity of 50%.
  • Alzheimer's disease and type 2 Diabetes are two yet incurable cell degenerative diseases. Protein misfolding and aggregation are be- lieved to be closely linked to their onset and pathogenesis.
  • MW low molecular weight
  • peptides and antibodies have been reported to prevent aggregation and formation of cytotoxic assemblies of ⁇ or IAPP in the past 20 years, only few of them have reached the stage of clini- cal studies and none of them is being currently therapeutically applicable (Citron M. Alzheimer's disease: strategies for disease modification. Nat Rev Drug Discov. 2010; 9: 387-98; Mullard A. Sting of Alzheimer's failures offset by upcoming prevention trials. Nat Rev Drug Discov. 2012; 1 1 : 657-60).
  • IAPP nonamyloidogenic and bioactive human islet amyloid polypeptide
  • pramlintide is an analogue of the natively nonamyloidogenic rat IAPP sequence which does not or only weakly inhibits amyloid formation and cytotoxicity by IAPP or A-beta (Yan LM, PNAS 2006, Angew. Chem. Int. Ed. 2007, see above) it is not expected to be a potent inhibitor of the cytotoxic aggregation process of these two polypeptides.
  • the technical problem underlying the present invention is to solve preferably the above-identified disadvantages and especially to provide sequences of synthetic peptides that are high affinity ligands of ⁇ or lAPP or both and inhibit preferably aggregation or misfolding of ⁇ and/or lAPP and cell degeneration by either ⁇ or lAPP or both of them and which could therefore find application in the treatment and non-invasive in vivo and/or in vitro diagnosis of Alzheimer's disease, type 2 Diabetes or both diseases. Furthermore, the synthetic peptides should be easily producible and saving thereby cost and time.
  • the present invention relates particularly to a peptide based compound for inhibiting aggregation, preferably fibrillogenesis, and/or toxicity of beta-amyloid peptide ( ⁇ ) and/or islet amyloid polypeptide (lAPP), wherein the peptide based compound comprises a C-terminal end CO-R and an N-terminal end NH-R' and is represented by formula (I), which is SEQ ID NO: 2-IC-SEQ ID NO: 3, wherein R is selected from the group consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of alkyl, haloalkyl, heteroalkyl, cycloalkyl, heter- ocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl, alkoxy, al
  • the sequence consisting of three units is a sequence, wherein the units are covalently linked with each other, preferably is a tripeptide.
  • SEQ ID No: 2 is covalently linked with the linker, preferably the inhibitory core, which is covalently linked with SEQ ID No: 3.
  • a peptide corresponding to a partial lAPP segment namely IAPP(8-28), or its double N-methylated version IAPP(8-28)-GI is unable to inhibit ⁇ or lAPP fibrillogenesis and cytotoxicity (Andreetto E, Yan LM, Caporale A, Kapurniotu A. Dissecting the role of single regions of an lAPP mimic and lAPP in inhibition of Abeta40 amyloid formation and cytotoxicity. ChemBioChem. 201 1 ; 12: 1313-22).
  • N-methylation improves preferably the inhibitory effects on lAPP or ⁇ aggregation and toxicity.
  • the N-methylated peptides have most likely an increased proteolytic stability towards serum proteases as compared to non-methylated ones which makes them promising candidates for therapeutics.
  • solubilising tags to the N- and C- terminal sequence parts of the peptide based compounds leads to improved solubility properties and improved inhibitory potentials.
  • the peptide based compounds are preferably able to bind with high affinity, preferably with a dissociation constant Kd smaller than 5 ⁇ , ⁇ or IAPP monomers and/or their fibrillar as- semblies.
  • Their ability to bind ⁇ or IAPP with high affinity is preferably independent of their effects on ⁇ or IAPP aggregation and toxicity suggesting a conformational specificity in their interaction with ⁇ or IAPP underlying their inhibitory effects on their aggregation and toxicity pathways. Therefore, the peptide based compounds are preferably promising compounds for the development of conformation specific ligands for the non-invasive detection of ⁇ or IAPP assemblies.
  • the peptide based compounds are preferably nanomolar affinity ligands of both ⁇ and IAPP binding both soluble ⁇ and IAPP and amyloid aggregates thereof. Based on these properties they can be used as non-invasive tracers for the detection of various forms of ⁇ and IAPP, namely their monomers, oligomers and/or amyloid plaques, in body fluids and/or tissues, after they are labelled.
  • the peptide based compounds can be easily synthesized, preferably in large scale, preferably via solid phase synthesis. Their preparation and purification is easier and significantly less expensive as compared to IAPP-GI, since their sequences are about half as long as the sequence of IAPP-GI or the usually high anti-amyloid MW (molecular weight) antibodies or affibodies.
  • the peptide based compounds are preferably soluble, nontoxic, nonamyloidogenic and nanomolar activity inhibitors of aggregation and toxicity of ⁇ , IAPP, or both and are able to block aggregation and toxicity of both ⁇ and IAPP in the nanomolar range.
  • the peptide based compounds according to the present invention are preferably significantly shorter which results in an easier and less expensive synthe- sis and purification and b) are preferably not bioactive - other than IAPP-GI and related IAPP mimics - as they do not preferably bind the IAPP receptor.
  • the N- and C-termini of the IAPP (amino acids 1 - 7 and 29 to 37) which are crucial for binding to the IAPP receptor are preferably not present in the peptide based compounds.
  • the peptide based compounds according to the present invention can be preferably applied as inhibitors of amyloid formation by ⁇ or IAPP or both of them without exhibiting IAPP receptor agonistic activity.
  • the peptide based compounds are preferably promising candidates for the development of bifunctional peptide-based drugs targeting protein aggregation and related cell degeneration in both type 2 Diabetes and Alzheimer's disease.
  • the SEQ ID NO: 2 and/or the SEQ ID NO: 3 are preferably modified by at least one N- alkylation, preferably at least one N-methylation.
  • at least one amino acid of the peptide based compounds according to the present invention comprise at least one artificially introduced moiety selected from the group consisting of alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylakyl, arylheteroalkyl, alkoxy, alkoxyalkyl and alkoxyaryl, wherein each moiety has 1 to 8 carbon atoms, preferably 3 to 6 carbon atoms.
  • the peptide based compounds according to the present invention are modified, wherein at least at one amino acid comprises at least one artificially introduced short moiety consisting of at least one carbon atom, at least one hydrogen atom and at least one het- ero atom, wherein the at least one hetero atom is selected from the group consisting of N, O and S, and the sum of the carbon atom(s) and the hetero atom(s) is between 1 to 10, preferably 2 to 8, preferably 3 to 7.
  • X3 preferably used in the tables and the examples herein, is understood as sequence of three X, wherein X is an amino ac- id, preferably abbreviated with the one letter code, or another chemical compound used in the inhibitory core of the peptide based compound according to the present invention.
  • R3 means Arg-Arg-Arg.
  • a peptide based compound according to the present invention is preferably a peptide based compound according to the present invention in combination with one or more preferred embodiments of the present invention.
  • the "peptide based compound” is a molecule comprising amino acids linked together through an am- ide bond, such as an oligopeptide, polypeptide or protein.
  • the peptide based compound can comprise solely amino acids, either in D- configuration or L-configuration or both.
  • the peptide based com- pound can also comprise in addition to naturally occurring amino acids artificially produced amino acids and/or other chemical compounds, especially chains, comprising at least one amino group and at least one carboxylic group.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the solubilising tag consists of at least three, preferably exactly three solubilising amino acids.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the at least three solubilising amino acids are selected from the group consisting of lysine, ornithine, aspartic acid, arginine and glutamic acid.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein at least one amino acid of the peptide based compound is N-methylated, that is amide bond N-methylated.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the at least one N-methylated amino acid is selected from the group consisting of Leucine-12, Alanine-13, Leucine-16, Valine-17, Glycine-24 and lsoleucine-26 (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ).
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the two N-methylated amino acids are Glycine-24 and lsoleucine-26 (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ).
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the four N-methylated amino acids are Leucine-12, Alanine-13, Leucine- 16 and Valine-17 (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ).
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the four N-methylated amino acids are Leucine-12, Leucine-16, Glycine- 24 and lsoleucine-26 (numbers corresponding to amino acid posi- tions of the full length IAPP protein represented by SEQ ID NO: 1 ).
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the six N-methylated amino acids are Leucine-12, Alanine-13, Leucine-16, Valine-17, Glycine-24 and lsoleucine-26 (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ).
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the inhibitory core is selected from the group consisting of Val-Val-Val, Leu-Leu-Leu, lle-lle-lle, Nle-Nle-Nle, (2-Aoc)-(2-Aoc)-(2-Aoc), Phe- Phe-Phe, ChA-ChA-ChA, Dap-Dap-Dap, Lys-Lys-Lys, Orn-Orn-Orn, Arg-Arg-Arg, Ala-Ala-Ala, Pro-Pro-Pro, Adc and Amba-Aba.
  • the inhibitory core is selected from the group consisting of Val-Val-Val, Leu-Leu-Leu, lle-lle-lle, Nle-Nle-Nle, (2-Aoc)-(2-Aoc)-(2-Aoc), Phe- Phe-Phe, ChA-Ch
  • the inhibitory core is selected from the group consisting of Val-Val-Val, Leu-Leu-Leu, lle-lle-lle, Nle-Nle-Nle, (2-Aoc)-(2-Aoc)-(2-Aoc), Phe-Phe-Phe, ChA-ChA-ChA, Dap-Dap- Dap, Arg-Arg-Arg and Ala-Ala-Ala.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention, wherein the peptide based compound is selected from the group consisting of the peptides represented by SEQ ID NOs: 4 to 53, preferably by SEQ ID NOs 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 38, 40, 41 , 47 and 48.
  • the present invention relates particularly to a peptide based compound according to the present invention for use in a method of prophylactic or therapeutic treatment of at least one amyloidogenic disease, preferably Alzheimer's diseases and/or Diabetes type 2.
  • the amyloidogenic disease is a protein aggregation disease.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention for use in a method according to the present invention, wherein the at least one amyloidogenic disease is Alzheimer's disease or type 2 Diabetes.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention for use in a method of prophylactic or therapeutic treatment of both Alzheimer's disease and type 2 Diabetes in a patient in need thereof.
  • the present invention relates especially to a peptide based compound according to the present invention for use in a method of non- invasive in vivo and/or in vitro diagnosis of at least one amyloidogenic disease, preferably Alzheimer's diseases and/or Diabetes type 2, wherein the peptide based compound comprises a C-terminal end CO-R and an N-terminal end NH-R' and is represented by formula (I), which is
  • R is selected from the group consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of alkyl, haloalkyi, heteroalkyl, cycloalkyl, heter- ocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl, alkoxy, alkoxyalkyl and alkoxyaryl, wherein R' is selected from the group consisting of -H, -CO-R 3 and a solubilising tag, wherein R 3 is selected from the group consisting of alkyl, haloalkyi, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkylalkyl, wherein R 3 is selected from the group consist
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention for use in a method of non-invasive in vivo and/or in vitro diagnosis of at least one amyloidogenic disease, preferably Alzheimer's diseases and/or Diabetes type 2, wherein the peptide based compound comprises a C-terminal end CO-R and an N-terminal end NH-R' and is represented by formula (I), which is SEQ ID NO: 2-IC-SEQ ID NO: 3, wherein R is selected from the group consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of alkyl, haloalkyl, heteroalkyl, cycloalkyl, heter- ocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl,
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention for use in a method of non-invasive in vivo and/or in vitro diagnosis of both Alzheimer's disease and type 2 Diabetes.
  • the peptide based compound according to the present invention acts preferably as conformation-specific ligand in the method of noninvasive in vivo and/or in vitro diagnosis of at least one amyloidogen- ic disease, preferably Alzheimer's diseases and/or Diabetes type 2.
  • the present invention relates in a preferred embodiment to a peptide based compound according to the present invention for use in a method according to the present invention, wherein the peptide based compound is labelled or derivatized in a suitable manner for use in an in vitro or non-invasive in vivo diagnosis system for at least one amyloidogenic disease, preferably Alzheimer's disease and/or type 2 Diabetes.
  • the peptide based compound influences preferably peptides which form amyloid or amyloidogenic structures with respect to their ability to aggregate or to misfold, preferably inhibits, reduces or blocks the aggregation and/or misfolding of said peptides.
  • the lag phase of aggregation is extended in comparison with the lag phase of naturally oc- curing amyloidogenic peptides by a factor of at least 1 .1 , preferably of at least 1 .5, preferably of at least 2, preferably of at least 10, pref- erably of at least 20, preferably of at least 100.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-Val-Val-Val-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is repre- sented by the formula (I) SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-Nle-Nle-Nle-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-(2-Aoc)-(2-Aoc)-(2-Aoc)- SEQ ID NO: 3, wherein 2-Aoc is 2-aminooctanoic acid and wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is repre- sented by the formula (I) SEQ ID NO: 2-Phe-Phe-Phe-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-ChA-ChA-ChA-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-Dap-Dap-Dap-SEQ ID NO: 3, wherein Dap is 2,3-diaminopropionic acid and wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-Arg-Arg-Arg-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) SEQ ID NO: 2-lle-lle-lle-SEQ ID NO: 3, wherein Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) Lys-Lys-Lys-SEQ ID NO: 2-Ala-Ala-Ala- SEQ ID NO: 3-Lys-Lys-Lys, wherein Gly-18 and lle-20 are preferably N-methylated.
  • the peptide based compound is represented by the formula (I) Lys-Lys-Lys-SEQ ID NO: 2-Leu-Leu-Leu- SEQ ID NO: 3-Lys-Lys-Lys, wherein Gly-18 and lle-20 are preferably N-methylated.
  • the peptide based compound is repre- sented by the formula (I) SEQ ID NO: 2-Ala-Ala-Ala-SEQ ID NO: 3, wherein Leu-5, Ala-6, Leu-9 Val-10, Gly-15 and lle-17 are preferably N-methylated.
  • the peptide based compound comprises a C-terminal end CO-R and a N-terminal end NH-R', wherein R is selected from the group consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of alkyl, haloalkyi, heteroalkyl, cycloalkyl, heter- ocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl, alkoxy, alkoxyalkyl and alkoxyaryl, wherein R' is selected from the group consisting of -H, -CO-R 3 and a solubilising tag, wherein R 3 is selected from the group consisting of alkyl, haloalkyi, hetero
  • the peptide based compound comprises a C-terminal end CO-R and a N-terminal end NH-R', wherein R is selected the group consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of alkyl, haloalkyi, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, arylheteroalkyl, alkoxy, alkoxyalkyl and alkoxyaryl, wherein R' is selected from the group consisting of -H, -CO-R 3 and a solubilising tag, wherein R 3 is selected from the group consisting of alkyl, haloalkyi, heteroalkyl, cycl
  • the peptide based compound comprises a C-terminal end CO-R and a N-terminal end NH-R', wherein R is selected from the group consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C6 heteroalkyl, C3 to C6 cycloalkyl, C3 to C6 heterocycloalkyl, C3 to C6 aryl, C3 to C6 heteroaryl, C3 to C6 arylalkyl, C3 to C6 heteroaryl C1 to C6 alkyl, C3 to C6 arylhetero C1 to C6 alkyl, C1 to C6 alkoxy, C1 to C6 alkoxy
  • the peptide based compound comprises a C-terminal end CO-R and a N-terminal end NH-R', wherein R is selected from the consisting of -OH, -NH 2 , -NHR 1 , -NR 1 R 2 and a solubilising tag, wherein R 1 and R 2 are the same or different and are selected from the group consisting of C1 to C6 alkyl, preferably methyl, wherein R' is selected from the group consisting of -H, -CO-R 3 and a solubilising tag, wherein R 3 is selected from the group consisting of C1 to C6 alkyl, preferably methyl, and wherein the solubilising tag is selected from the group of peptides consisting of three amino acids, which can be the same or different, preferably the same, and are selected from the group consisting of Lys, Orn, Asp, Arg and Glu, preferably Lys and
  • the peptide based compound according to the present invention preferably SEQ ID NO: 2-(2-Aoc)-(2-Aoc)- (2-Aoc)-SEQ ID NO: 3, wherein 2-Aoc is 2-aminooctanoic acid, wherein Gly-15 and lle-17 are preferably N-methylated, and/or SEQ ID NO: 2-Ala-Ala-Ala-SEQ ID NO: 3, wherein Leu-5, Ala-6, Leu-9 Val-10, Gly-15 and lle-17 are preferably N-methylated, inhibits, preferably strongly, the IAPP aggregation and toxicity.
  • the peptide based compound according to the present invention preferably selected from SEQ ID NO: 2-Arg- Arg-Arg-SEQ ID NO: 3, SEQ ID NO: 2-lle-lle-lle-SEQ ID NO: 3, SEQ ID NO: 2-Phe-Phe-Phe-SEQ ID NO: 3, SEQ ID NO: 2-Val-Val-Val- SEQ ID NO: 3, SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3 and Lys- Lys-Lys-SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3-Lys-Lys-Lys, wherein Gly-22 and lle-24 are preferably N-methylated (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ), inhibits, preferably strongly, the ⁇ aggregation and toxicity.
  • the peptide based compound according to the present invention preferably selected from SEQ ID NO: 2-Nle- Nle-Nle-SEQ ID NO: 3, SEQ ID NO: 2-ChA-ChA-ChA-SEQ ID NO: 3, SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3 and Lys-Lys-Lys-SEQ ID NO: 2-Ala-Ala-Ala-SEQ ID NO: 3-Lys-Lys-Lys, wherein Gly-22 and lle-24 are preferably N-methylated (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ), inhibits, preferably strongly, both the IAPP and ⁇ aggregation and toxicity.
  • At least one peptide based compound preferably a mixture of at least two peptide based compounds, preferably exactly one peptide based compound, according to the present invention, preferably selected from SEQ ID NO: 2-Ala-Ala-Ala- SEQ ID NO: 3, wherein Leu-5, Ala-6, Leu-9 Val-10, Gly-15 and lle-17 are preferably N-methylated, and SEQ ID NO: 2-(2-Aoc)-(2-Aoc)-(2- Aoc)-SEQ ID NO: 3, wherein 2-Aoc is 2-amino-octanoic acid and wherein Gly-15 and lle-17 are preferably N-methylated, is used in a method of prophylactic or therapeutic treatment of Diabetes type 2, especially for inhibiting at least partially, preferably completely, the aggregation and/or misfolding of the islet amyloid polypeptide, preferably of SEQ ID NO: 1 .
  • At least one peptide based compound preferably a mixture of at least two peptide based compounds, preferably exactly one peptide based compound, according to the present invention, preferably selected from SEQ ID NO: 2-Arg-Arg-Arg- SEQ ID NO: 3, SEQ ID NO: 2-Phe-Phe-Phe-SEQ ID NO: 3, SEQ ID NO: 2-Val-Val-Val-SEQ ID NO: 3, SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3 and Lys-Lys-Lys-SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3-Lys-Lys-Lys, wherein Gly-24 and lle-26 are preferably N- methylated (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ), is used in a method of prophylactic or therapeutic treatment of Diabetes type 2, especially for inhibiting at least partially, preferably completely, the aggregation
  • At least one peptide based compound preferably a mixture of at least two peptide based compounds, pref- erably exactly one peptide based compound, according to the present invention, preferably selected from SEQ ID NO: 2-Nle-Nle-Nle- SEQ ID NO: 3, SEQ ID NO: 2-ChA-ChA-ChA-SEQ ID NO: 3, SEQ ID NO: 2-Leu-Leu-Leu-SEQ ID NO: 3 or Lys-Lys-Lys-SEQ ID NO: 2- Ala-Ala-Ala-SEQ ID NO: 3-Lys-Lys-Lys, wherein Gly-24 and lle-26 are preferably N-methylated (numbers corresponding to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ), is used in a method of prophylactic or therapeutic treatment of Alzheimer's disease and Diabetes type 2, especially for inhibiting at least partially, preferably completely, the aggregation and/or misfold--
  • At least one peptide based compound preferably a mixture of at least two peptide based compounds, preferably exactly one peptide based compound, according to the present invention is used in a method of prophylactic or therapeutic treatment of Alzheimer's disease, especially for inhibiting at least partially, preferably completely, the aggregation and/or misfolding of beta-amyloid peptide, preferably of SEQ ID NOs: 55 and/or 56.
  • said aggregation and/or misfolding forming of cell toxic oli- gomers and amyloid fibrils, preferably in blood and cerebrospinal fluid is preferably prevented at least partially, preferably completely.
  • At least one peptide based compound preferably a mixture of at least two peptide based compounds, pref- erably exactly one peptide based compound, according to the present invention is used in a method of prophylactic or therapeutic treatment of Diabetes type 2, especially for inhibiting at least partially, preferably completely, the aggregation and/or misfolding of islet amyloid polypeptide, preferably of SEQ ID NO: 1 .
  • pancreatic beta-cell damage and/or Diabetes type 2 pathogenesis is preferably prevented at least partially, preferably completely.
  • At least one peptide based compound preferably a mixture of at least two peptide based compounds, pref- erably exactly one peptide based compound, according to the present invention is used in a method of prophylactic or therapeutic treatment of Alzheimer's disease and Diabetes type 2, especially for inhibiting at least partially, preferably completely, the aggregation and/or misfolding of beta-amyloid peptide and islet amyloid polypep- tide, preferably of SEQ ID NOs: 1 and 55 and/or 1 and 56.
  • the peptide based compound according to the present invention is preferably a highly potent inhibitor of cytotoxic self-assembly and/or fibrillogenesis of ⁇ , lAPP, or both ⁇ and lAPP, wherein lAPP is preferably represented by SEQ ID NO: 1 and ⁇ by SEQ ID NO: 55 and/or 56.
  • the peptide based compound according to the present invention is preferably a high affinity ligand of ⁇ , IAPP, or both ⁇ and IAPP, wherein IAPP is preferably represented by SEQ ID NO: 1 and ⁇ by SEQ ID NO: 55 and/or 56.
  • the peptide based compound is preferably produced by using the IAPP "hot spot regions" of the ⁇ - ⁇ cross-interaction interface SEQ ID NO:2, that is IAPP(8-18), and SEQ ID NO:3, that is IAPP(22- 28), as molecular templates (see Figure 1 ). These hot regions are covalently linked to each other by applying various different inhibitory cores, abbreviated as IC.
  • At least one, preferably exactly one, preferably a mixture of peptide based compound(s) is used in a method of non-invasive in vivo and/or in vitro diagnosis of an amyloidogenic disease, preferably Alzheimer's disease or Diabetes type 2, by binding with high affinity to beta-amyloid peptide and islet amyloid polypeptide, preferably to at least one polypeptide selected from SEQ ID NOs: 1 , 55 and 56, preferably in their monomer, oligomer or amyloid fibril state.
  • the method of non-invasive in vivo and/or in vitro diagno- sis of an amyloidogenic disease is preferably a non-invasive in vivo diagnosis.
  • said non-invasive in vivo and/or in vitro diagnosis, construed as assay system can be used for quantification of beta-amyloid peptide and islet amyloid polypeptide, preferably of at least one polypeptide selected from SEQ ID NO: 1 , 55 and 56, pref- erably in their monomer, oligomer or amyloid fibril state.
  • the peptide based compounds are used in a method of non-invasive in vivo and/or in-vitro diagnosis of at least one amyloidogenic disease, wherein the method of in-vitro diagnosis is preferably ELISA (Enzyme Linked Immunosorbent Assay) or RIA (Radioimmunoassay).
  • the peptide based compound is used together prefera- bly with a marker, preferably with a spin label or fluorescence or luminescence marker, especially in an N-terminal-label, preferably in an N-terminal biotinylated, form or N-terminal fluorescein-labelled form or labelled with another fluorescent marker.
  • the method of noninvasive in vivo diagnosis is preferably a PET (Positron Emission Tomography) und SPECT (Single Photon Emission Computed Tomography) based detection of aggregate forms of ⁇ or IAPP associated with Alzheimer's disease and type 2 Diabetes pathogenesis.
  • the peptide based compound is preferably labelled, preferably N-terminal, with a marker for PET which can be the mark- er 1 ,4,7,10-tetraazacyclododecane-1 ,4,7,10-tetraacetic acid (DOTA).
  • the DOTA comprises preferably additionally a metal ion, preferably gallium.
  • the peptide based compound comprises at least one amino acid being N- methylated.
  • An N-methylated amino acid is an amino acid in which a hydrogen atom of the a-amino group of the amino acid is replaced by a methyl group.
  • the peptide based compound are labelled in particular at the N-terminal a-amino group, in particular with an acetyl group, a radioactive marker, an enzyme marker, fluorescent marker, luminescent marker or a spin label, a marker for PET or SPECT, preferably in such a way that said marker is joined to the peptide based compound by means of a spacer, which is preferably an amino acid.
  • the peptide based compound is selected from the group consisting of the com- pounds in table 1 and/or 2.
  • Figure 1 shows primary structures of ⁇ and lAPP.
  • the regions IAPP(8-18) and IAPP(22-28) are the lAPP regions which have been identified as hot regions of the ⁇ - ⁇ ( ⁇ 40 or ⁇ 42) interaction interface.
  • Figure 2 shows in the upper part sequences of lAPP and IAPP-GI which is the potent inhibitor of lAPP and ⁇ 40 or ⁇ 42 aggregation and toxicity and in the lower part an inhibitor design concept, basic structures, and classes of designed ligands and inhibitors of aggregation and toxicity of IAPP and ⁇ (see also Tables 1 , 2).
  • Figure 3 shows the results of assays reporting on kinetics of formation of amyloid fibrils via the amyloid specific ThT binding assay (Figure 3A) and cytotoxic aggregates via the MTT reduction assay in aged (0 h - 7 days) solutions of ⁇ alone or mixtures of ⁇ with each peptide based compound as indicated. Cytotoxicity of the aged solutions of ⁇ alone and the mixtures with each of the peptide based compounds was determined at the incubation time point of 72 h ( Figure 3B) or 7 days ( Figure 3C). The presented data is means ( ⁇ SEM (scanning electron microscope)) of 3 assays (performed in triplicates).
  • Figure 4 shows the results of assays reporting on kinetics of formation of amyloid fibrils via the amyloid specific ThT binding assay (Figure 4A) and cytotoxic aggregates via the MTT reduction assay in aged (0 h - 7 days) solutions of ⁇ alone or mixtures of ⁇ with each of the peptide based compounds as indicated. Cytotoxicity of the aged solutions of ⁇ alone and the mixtures with each of the peptide based compounds was determined at the incubation time point of 72 h ( Figure 4B) or 7 days ( Figure 4C). The presented data is means ( ⁇ SEM) of 3 assays (performed in triplicates).
  • Figure 5 shows the results of assays reporting on kinetics of formation of amyloid fibrils via the amyloid specific ThT binding assay (Figure 5A) and cytotoxic aggregates via the MTT reduction assay in aged (0 h - 7 days) solutions of ⁇ alone or mixtures of ⁇ with each of the peptide based compounds as indicated. Cytotoxicity of the aged solutions of ⁇ alone and the mixtures with each of the peptide based compounds was determined at the incubation time point of 72 h ( Figure 5B) or 7 days ( Figure 5C). The presented data is means ( ⁇ SEM) of 3 assays (performed in triplicates).
  • Figure 6 shows the results of assays reporting on kinetics of for- mation of amyloid fibrils via the amyloid specific ThT binding assay (Figure 6A) and cytotoxic aggregates via the MTT reduction assay in aged (0 h - 7 days) solutions of IAPP alone or mixtures of IAPP with each of the peptide based compounds as indicated. Cytotoxicity of the aged solutions of IAPP alone and the mixtures with each of the peptide based compounds was determined at the incubation time point of 24 h ( Figure 6B) or 7 days ( Figure 6C). The presented data is means ( ⁇ SEM) of 3 assays (performed in triplicates).
  • Figure 7 shows the results of assays reporting on kinetics of formation of amyloid fibrils via the amyloid specific ThT binding assay (Figure 7A) and cytotoxic aggregates via the MTT reduction assay in aged (0 h - 7 days) solutions of IAPP alone or mixtures of IAPP with each of the peptide based compounds as indicated. Cytotoxicity of the aged solutions of IAPP alone and the mixtures with each of the peptide based compounds was determined at the incubation time point of 24 h ( Figure 7B) or 7 days ( Figure 7C). The presented data is means ( ⁇ SEM) of 3 assays (performed in triplicates).
  • Figure 8 shows the results of assays reporting on kinetics of formation of amyloid fibrils via the amyloid specific ThT binding assay (Figure 8A) and cytotoxic aggregates via the MTT reduction assay in aged (0 h - 7 days) solutions of A alone or mixtures of ⁇ with peptide based compounds (L3-GI or L3) as indicated. Cytotoxicity of the aged solutions of ⁇ alone and the mixtures with each of the peptide based compounds was determined at the incubation time point of 72 h ( Figure 8B) or 7 days ( Figure 8C). The presented data is means ( ⁇ SEM) of 3 assays (performed in triplicates).
  • Table 1 shows sequences of representative compounds of classes (a) inhibitors/amyloid ligands described herein.
  • Table 2 shows sequences of representative compounds of classes (b)-(d) inhibitors/amyloid ligands described herein.
  • ⁇ beta-amyloid peptide
  • Adc amino decanoic acid, preferably 10-amino deca- noic acid
  • Amba-Aba p-aminomethylbenzoic acid covalently linked via amid bond with p-amino benzoic acid
  • Aoc 8-amino octanoic acid
  • IAPP islet amyloid polypeptide
  • IAPP-GI [(N-Me)G24, (N-Me)l26]-IAPP
  • N-methylated positions correspond to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 .
  • the peptide based compounds were classified in "highly potent” inhibitors (++++ in Table 3) when they were found to be able to block ⁇ fibril formation and toxicity up to the incubation time point of 7 days and in “medium potency” inhibitors ("++" in Table 3) when they were found to be able to inhibit ⁇ fibril formation and toxicity up to the 72 h incubation time point. Finally, peptide based compounds were classified in “no inhibitors” when they had no effect on formation of fibrils and cytotoxic aggregates ("- -" in Table 3).
  • peptide based compounds with linker sequences L3 and V3 are highly potent inhibitors.
  • the A3- linker containing peptide based compound is a medium potency in- hibitor and the G3-linked one has no effect whatsoever on ⁇ aggregation and toxicity.
  • IAPP(8-28)-GI has also no effect on aggregation and toxicity of ⁇ as previously reported (Andreetto E, 201 1 , above).
  • the segments IAPP(8-18), IAPP(22-28), and IAPP(22- 28)-GI alone are unable to affect fibrillogenesis and cytotoxicity of ⁇ as well (Andreetto E, 201 1 , above).
  • N-methylated corresponds to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1
  • peptide based compounds K3-GI, KAc3-GI, R3-GI, and Dap3-GI containing polar charged residues in the linker sequence on ⁇ fibrillogenesis and cytotoxicity are studied and compared to each other ( Figure 4). Ki- netics of fibrillogenesis (Fig. 4A) and formation of cytotoxic assemblies (Fig. 4B and 4C) were determined as described above under Example 1 .
  • the peptide based compounds are classified (Table 3) with regard to their inhibitory potential according to the same criteria as defined in Example 1 .
  • N-methylated corresponds to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1
  • peptide based compounds L3-GI, Nle3-GI, F3-GI, ChA3-GI (ChA, Cyclohexylala- nine), and 2-Aoc3-GI (Aoc, 2-aminooctanoic acid) containing various different hydrophobic residues in the linker sequence on ⁇ fibrillo- genesis and cytotoxicity are studied and compared to each other (Figure 5).
  • Kinetics of fibrillogenesis Fig. 5A
  • formation of cyto- toxic assemblies Fig. 5B and 5C
  • the analogues are classified (Table 3) with regard to their inhibitory potentials according to the same criteria as defined in Example 1 .
  • the peptide based compounds with L3, Nle3, and F3 linkers are highly potent inhibitors while the 2-Aoc3 linker containing peptide based compound does not significantly affect ⁇ aggregation and toxicity and the ChA3 linker containing peptide based compound is medium potency inhibitor.
  • IAPP cytotoxic oligomers in a time and concentration-dependent manner and experimental assay systems has been established to study in vitro kinetics of IAPP fibril- logenesis and toxicity (Yan LM, 2006, above; Yan LM, 2007, above).
  • kinetics of IAPP fibrillogenesis were determined by in- cubating IAPP (16.5 ⁇ in 50 mM sodium phosphate buffer, pH 7.4, containing 100 mM NaCI and 0.5% HFIP) and 1 :2 mixtures of IAPP with analogues (16.5 ⁇ IAPP and 33 ⁇ each of the analogues in 50 mM sodium phosphate buffer, pH 7.4, containing 100 mM NaCI and 0.5% HFIP) for up to 7 days at room temperature.
  • analogues (16.5 ⁇ IAPP and 33 ⁇ each of the analogues in 50 mM sodium phosphate buffer, pH 7.4, containing 100 mM NaCI and 0.5% HFIP)
  • N-methylated positions correspond to amino acid positions of the full length IAPP protein represented by SEQ ID NO: 1 ) which was present in all class (b) and (c) analogues on the inhibitory potential of the peptide based compounds on ⁇ aggregation and toxicity.
  • L3-GI is a highly potent inhibitor while L3 is a medium potency inhibitor (at the 1 :1 molar ratio to ⁇ applied here) and in fact similar results were obtained with regard to the inhibitory effecs of IAPP as well (data not shown). These results are consistent with the presence of the double N-methylation at G24 and I26 resulting in improved inhibitory potentials on ⁇ and IAPP fibrillogenesis and cytotoxicity.
  • High inhibitory potency indicates inhibitory effect of the peptide based compound on formation of cytotoxic aggegates by ⁇ or IAPP following incubation for up to 7 days; medium potency indicates inhibitory effect on formation of cytotoxic aggregates following incubation for up to 24 h for IAPP or 72 h for ⁇ as determined in vitro using the experimental assay systems described in Examples 1 to 6.
  • This Table demonstrates the different effects of the various different linker sequences on the inhibitory potential of the IAPP(8-28)-GI analogue peptide based compounds on ⁇ and IAPP fibril formation and cytotoxicity.
  • Table 3 shows a summary of the effects of several of the class (b) and (c) peptide based compounds, IAPP(8-28)-GI, and each of the linked sequences alone on formation of cytotoxic aggregates of ⁇ or IAPP.
  • the effects are classified in: "++”, corresponding to medium inhibitory potency; "++++”, corresponding to high inhibitory potency; "+”, corresponding to very weak inhibitory potency; and corresponding to no inhibitory potency (see text under Example 1 ).
  • Table 4 a summary of the IC50 values of the effects of highly potent peptide based compounds on formation of cytotoxic ⁇ or IAPP assemblies is presented.
  • the assays for the determination of the IC50 values were performed by using mixtures of ⁇ or IAPP (at 100 nM) with various amounts of the analogues under the same experimental set-up as described in Examples 1 to 6 and in references Yan LM, 2006, above; Yan LM, 2007, above; Yan LM, 2013, above).
  • IC50s were determined in 3 days aged incubations of ⁇ alone or its mixtures with analogues and in 24 h aged incubations of IAPP alone or its mixtures with the peptide based compound as described (Yan LM, 2013, above).
  • the IC50 values shown in Table 4 are means ( ⁇ SEM) from 3 assays.
  • Table 4 shows IC50 values of effects of some of the highly potent analogues on formation of cytotoxic ⁇ or IAPP assemblies.
  • Example 9 In Table 5 a summary of the apparent (app.) binding affinities of the interactions of the peptide based compounds with IAPP or ⁇ as determined by fluorescence spectroscopic titrations is presented.
  • the underlying principle of this kind of assay is that changes in the fluorescence emission of fluorescently labelled proteins are highly sensitive indicators of changes in the environment of the fluorophore that might be caused by ligand binding (Eftink MR. Fluorescence methods for studying equilibrium macromolecule-ligand interactions. In: Brand L, Johnson ML, editors. Methods in Enzymology: Fluorescence Spectroscopy. San Diego: Academic Press; 1997. p. 221 -57).
  • the experimental assay system applied to quantify the app. affinities (app.
  • ⁇ or IAPP fibrils were prepared from aged ⁇ or IAPP solutions (for ⁇ fibrils incubation conditions were: 16.5 ⁇ in 50 mM sodium phosphate buffer, pH 7.4, containing 100 mM NaCI and 1 % HFIP; for IAPP fibrils incubation conditions were: 16.5 ⁇ in 50 mM sodium phosphate buffer, pH 7.4, containing 100 mM NaCI and 0.5% HFIP) as described under references (Yan LM, 2007, above; Yan LM, 2013, above).
  • Table 5 shows apparent binding affinities (app. Kd) of interactions of peptide based compounds with ⁇ or IAPP (monomeric or fibrillar assemblies) as determined by fluorescence spectroscopic titrations.
  • Kds shown are means from 3 assays in the case of Kds for the interaction with monomers and from one assay in the case of app. Kds for the interaction with fibrillar assemblies.

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Abstract

La présente invention concerne un composé à base de peptide et son utilisation dans une méthode de traitement prophylactique ou thérapeutique d'au moins une maladie amyloïdogène ou son utilisation dans une méthode diagnostique non invasive in vivo et/ou in vitro d'au moins une maladie amyloïdogène (agrégation de protéines).
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WO2018220393A1 (fr) * 2017-06-02 2018-12-06 University Of Lancaster Peptides d'amyline
CN113614101A (zh) * 2019-02-22 2021-11-05 洛约拉马利蒙特大学 淀粉样肽的变体

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018220393A1 (fr) * 2017-06-02 2018-12-06 University Of Lancaster Peptides d'amyline
CN113614101A (zh) * 2019-02-22 2021-11-05 洛约拉马利蒙特大学 淀粉样肽的变体

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