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US-12616760-B2 - Synthetic cyclic peptide mimetics

US12616760B2US 12616760 B2US12616760 B2US 12616760B2US-12616760-B2

Abstract

Described herein are synthetic cyclic peptide mimetics comprising alternating D-amino acids and L-amino acids and amino acid derivatives, such as aza-amino acids and azasulfuryl-amino acids. Optionally, the cyclic peptide mimetics may be conjugated to another agent via a linker to form cyclic peptide mimetic conjugates. The cyclic peptide mimetics described herein may be used as diagnostic or therapeutic agents for diagnosis or treatment of amyloidogenic diseases.

Inventors

  • Shai Rahimipour
  • Brigitte Guerin
  • Maram HABASHI
  • Michal Richman
  • William Lubell
  • Pradeep Chauhan
  • Suresh VUTLA
  • RAMESH CHINGLE
  • Samia Ait-Mohand
  • Veronique DUMULON-PERREAULT

Assignees

  • BAR ILAN UNIVERSITY
  • Université de Montréal
  • SOCIETE DE COMMERCIALISATION DES PRODUITS DE LA RECHERCHE APPLIQUEE SOCPRA SCI

Dates

Publication Date
20260505
Application Date
20210913

Claims (18)

  1. 1 . A cyclic peptide mimetic having the structure c (X 1 -X 2 -X 3 -X 4 -X 5 -X 6 ) wherein: each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either an L-amino acid residue, a D-amino acid residue, or X 7 ; and wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is defined as X 7 ; and wherein the remaining X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 which are not defined as X 7 are amino acid residues in alternating L-configuration and D-configuration; wherein X 7 is an aza-amino acid residue or azasulfuryl-amino acid residue having the structure: wherein the R group is the same R group as defined in naturally occurring and synthetic amino acids; R 1 is hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, aryl alkyl or heteroaryl alkyl, or R 1 and R could together form a cyclic ring; Z is a carbonyl group of an adjacent amino acid residue; X is an amine group of an adjacent amino acid residue; and wherein each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either unsubstituted or substituted by a conjugate moiety.
  2. 2 . The cyclic peptide mimetic according to claim 1 , wherein: X 1 , X 3 and X 5 are each independently an amino acid residue having a D-configuration, or X 7 ; X 2 , X 4 and X 6 are each independently an amino acid residue having an L-configuration or X 7 ; and wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is defined as X 7 ; and wherein each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either unsubstituted or substituted by a conjugate moiety.
  3. 3 . The cyclic peptide mimetic according to claim 1 , wherein: X 1 , X 3 and X 5 are each independently an amino acid residue having an L-configuration, or X 1 ; X 2 , X 4 and X 6 are each independently an amino acid residue having a D-configuration or X 7 ; and wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is defined as X 1 ; and wherein each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either unsubstituted or substituted by a conjugate moiety.
  4. 4 . The cyclic peptide mimetic according to claim 3 wherein: X 1 is a D-Leu, D-Nle, D-tert-leucine, D-Ile residue or X 7 ; X 2 is a L-Nle, L-Leu, L-tert-leucine, L-Ile residue or X 7 ; X 3 is a D-Trp, D-Phe, D-Nal residue or X 7 ; X 4 is a L-His, L-Asn residue or X 7 ; X 5 is a D-Ser, D-Hse residue or X 7 ; and X 6 is a L-Lys, L-Orn, L-Arg residue or X 7 ; and wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is defined as X 7 ; and wherein each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either unsubstituted or substituted by a conjugate moiety.
  5. 5 . The cyclic peptide mimetic according to claim 1 , having a structure selected from the group consisting of: c(D-Leu-L-Nle-D-Trp-L-His-D-Ser-X 7 ) c(D-Leu-L-Nle-D-Trp-L-His-X 7 -L-Lys) c(D-Leu-L-Nle-D-Trp-X 7 -D-Ser-L-Lys) c(D-Leu-L-Nle-X 7 -L-His-D-Ser-L-Lys) c(D-Leu-X 7 -D-Trp-L-His-D-Ser-L-Lys) c(X 7 -L-Nle-D-Trp-L-His-D-Ser-L-Lys); and c(D-Leu-L-Nle-D-Trp-D-His-X 7 -L-Lys) and wherein each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either unsubstituted or substituted by a conjugate moiety.
  6. 6 . The cyclic peptide mimetic according to claim 1 , having a structure selected from the group consisting of: c(D-Leu-L-Nle-D-Trp-L-His-D-Ser-Gly*) c(D-Leu-L-Nle-D-Trp-L-His-Gly*-L-Lys) c(D-Leu-L-Nle-D-Trp-Gly*-D-Ser-L-Lys) c(D-Leu-L-Nle-Gly*-L-His-D-Ser-L-Lys) c(D-Leu-Gly*-D-Trp-L-His-D-Ser-L-Lys) c(Gly*-L-Nle-D-Trp-L-His-D-Ser-L-Lys) c(D-Leu-L-Nle-D-Trp-L-His-D-Ser-Lys*) c(D-Leu-L-Nle-D-Trp-L-His-Hse*-L-Lys) c(D-Leu-L-Nle-D-Trp-L-His-IPrTyr*-L-Lys) c(D-Leu-L-Nle-D-Trp-D-His-IPrTyr*-L-Lys) c(D-Leu-L-Nle-D-Trp-Phe*-D-Ser-L-Lys) c(D-Leu-L-Nle-D-Trp-Tal*-D-Ser-L-Lys) c(D-Leu-L-Nle-D-Trp-Pra*-D-Ser-L-Lys) c(D-Leu-L-Nle-Itr*-L-His-D-Ser-L-Lys) c(D-Leu-Nle*-D-Trp-L-His-D-Ser-L-Lys) c(D-Leu-Phe*-D-Trp-L-His-D-Ser-L-Lys) c(Leu*-L-Nle-D-Trp-L-His-D-Ser-L-Lys) c(Phe*-L-Nle-D-Trp-L-His-D-Ser-L-Lys) c(4-Phe*-L-Nle-D-Trp-L-His-D-Ser-L-Lys) and c(D-Leu-L-Nle-D-Trp-L-His-Gly ∧ -L-Lys), wherein an asterisk next to the amino acid code indicates that it is an aza-amino acid residue, having an R group corresponding to the specified amino acid residue, and a caret next to the amino acid code indicates that it is an azasulfuryl-amino acid residue having an R group corresponding to the specified amino acid residue, and wherein Nle is norleucine; Hse is homoserine, Tal is triazole-3-alanine, Itr is isotryptophan, IPrTyr is O-isopropyl-tyrosine, Pra is propargyl glycine and 4F-Phe is 4-fluoro phenylalanine; and wherein each of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is either unsubstituted or substituted by a conjugate moiety.
  7. 7 . The cyclic peptide mimetic according to claim 1 wherein one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is substituted by a conjugate moiety selected from the group consisting of: a protein, a peptide, a nanoparticle, a chelating moiety, a liposome, or a polymer.
  8. 8 . The cyclic peptide according to claim 7 wherein the conjugate moiety is a chelating moiety selected from the group consisting of: NOTA (2-[4,7-bis(carboxymethyl)-1,4,7-triazonan-1-yl]acetic acid) or its derivatives; DOTA (2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetic acid) or its derivatives; methylhydroxamates derived from triaza- and tetraazamacrocycles (NOTHA 2 and DOTHA 2 ) or its derivatives; 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) or its derivatives; diethylenetriaminepentaacetate (DTPA) or its derivatives; 1,4,7,10-tetraazadodecane-1,4,7-triacetate (D03A) and its derivatives; 3,6,9,15-tetraazabicyclo[9.3.1]pentadeca-1(1 5),11,13-triene-3,6,9-triacetic acid) (PCTA) or its derivatives; 1,4,7,10-tetraazacyclotridecanetetraacetic acid (TRITA) and its derivatives; 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA) and its derivatives; 1,4,7,10-tetraazadodecanetetramethylacetate (DOTMA) and its derivatives; 1,4,7,10-tetraazadodecane-1,4,7-trimethylacetate (D03MA) and its derivatives; N,N′,N″,N′″-tetraphosphonatomethyl-1,4,7,10-tetraazacyclododecane (DOTP) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene methylphosphonic acid) (DOTMP) and its derivatives; 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrakis(methylene phenylphosphonic acid) (DOTPP) and its derivatives; or N,N′-ethylenedi-L-cysteine or its derivatives; and N1,N1′-(butane-1,4-diyl)bis(N4-hydroxy-N1-(3-(4-(hydroxy(methyl)amino)-4-oxobutanamido) propyl)-N4-methylsuccinamide) (4HSM) or its derivatives.
  9. 9 . The cyclic peptide mimetic according to claim 7 wherein the conjugate moiety is a polyethylene glycol.
  10. 10 . The cyclic peptide mimetic according to claim 7 wherein the conjugate moiety is a fluorescent probe.
  11. 11 . The cyclic peptide mimetic according to claim 7 wherein the conjugate moiety is bound to an amine group of an R group of an amino acid residue.
  12. 12 . The cyclic peptide mimetic according to claim 1 wherein each one of X 1 , X 2 , X 3 , X 4 , X 5 , and X 6 is unsubstituted by a conjugate moiety.
  13. 13 . A conjugate comprising a peptide mimetic according to claim 1 and at least one nanoparticle or at least one radioactive metal.
  14. 14 . The conjugate according to claim 13 wherein the radioactive metal is selected from the group consisting of: Copper-64, Copper-67, Gallium-67, Gallium-68, Antimony-117, Antimony-119, Scandium-43, Scandium-44, Scandium-47, Titanium-45, Indium-111, Samarium-153, Strontium-89, Yttrium-90, Lutetium-177, Bismuth-213 and Actinium-225.
  15. 15 . A method for treatment of an amyloidogenic disease in a patient in need thereof comprising administering to the patient a cyclic peptide mimetic according to claim 1 or a conjugate comprising the cyclic peptide mimetic.
  16. 16 . The method according to claim 15 wherein the patient suffers from a disease selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Huntington's Disease, a prion disease, systemic amyloidosis, cataract, and ALS.
  17. 17 . A method for imaging a subject comprising administering to the subject a cyclic peptide mimetic according to claim 1 or a conjugate comprising it, and performing on the subject positron emission computed tomography (PET); single-photon emission computed tomography (SPECT), CT, or magnetic resonance imaging (MRI).
  18. 18 . A method for early imaging of an amyloid beta in a subject suspected of amyloidogenic pathology comprising administering to the subject a cyclic peptide mimetic according to claim 1 or a conjugate comprising it, and performing on the subject positron emission computed tomography (PET); single-photon emission computed tomography (SPECT), CT, or magnetic resonance imaging (MRI).

Description

CROSS REFERENCE TO RELATED APPLICATIONS This is the US National Stage of International Patent Application No. PCT/IL2021/051106 filed Sep. 13, 2021, and benefit is claimed to U.S. Provisional Patent Application No. 63/077,627 filed Sep. 13, 2020; the contents of which is incorporated by reference herein in its entirety. FIELD Embodiments relate to synthetic cyclic peptide mimetics and their uses for treatment or diagnosis of disease. BACKGROUND Amyloidogenic diseases are characterized by the aggregation of normally soluble proteins into insoluble fibrils in intracellular and extracellular spaces. The amyloid fibrils are usually composed of cross β-sheet structures, which are resistant to metabolic degradation. Amyloidogenic diseases are progressive disorders associated with ageing, morbidity, and high mortality rates. Approximately 50 different peptides and proteins are implicated in amyloid diseases: e.g., amyloid-β (Aβ) in Alzheimer's disease (AD), α-synuclein (α-syn) in Parkinson's disease (PD), Huntingtin protein in Huntington's disease (HD) and amylin in type II diabetes. Amyloidogenic protein fibrils share typically common structural and biochemical properties irrespective of sequence and chain length. Their similar β-sheet structure features a characteristic cross β-conformation, which can cross-interact and cross-seed with different amyloids in vitro and in vivo to form homogeneous or heterogeneous amyloidogenic protein aggregates. Amyloid proteins share also common functional activities and interact similarly with a variety of membranes to generate channels and pores leading to cellular toxicity. SUMMARY Described herein are synthetic cyclic peptide mimetics comprising alternating D-amino acids and L-amino acids and amino acid derivatives, such as aza-amino acids and azasulfuryl-amino acids. Optionally, the cyclic peptide mimetics may be conjugated to another agent via a linker to form cyclic peptide mimetic conjugates. The agent may be, for example, a chelating group to bind to a metal or an ion in a conjugate, which may be radioactive, which acts as an aid in diagnosis or treatment of an amyloidogenic disease. The agent may be also a thiol to bind a nanoparticle such as gold or iron nanoparticles acting as contrasting agents or as delivery vehicles. According to an embodiment, the cyclic peptide mimetic has the structure c(X1-X2-X3-X4-X5-X6) wherein: each of X1, X2, X3, X4, X5, and X6 is either an L-amino acid residue, a D-amino acid residue, or X7; and wherein one of X1, X2, X3, X4, X5, and X6 is defined as X7; and wherein the remaining X1, X2, X3, X4, X5, and X6 which are not defined as X7 are amino acid residues in alternating L-configuration and D-configuration; wherein X7 is an aza-amino acid residue or azasulfuryl-amino acid residue having the structure: wherein the R group is the same R group as defined in naturally occurring and synthetic amino acids; R1 is hydrogen, alkyl, aryl, heteroalkyl, heteroaryl, aryl alkyl or heteroaryl alkyl, or R1 and R could together form a cyclic ring; Z is a carbonyl group of an adjacent amino acid residue; X is an amine group of an adjacent amino acid residue; and wherein each of X1, X2, X3, X4, X5, and X6 is either unsubstituted or substituted by a conjugate moiety. Additionally, described herein are methods for treatment and for diagnosis of amyloidogenic diseases comprising administering to a patient in need thereof a synthetic cyclic peptide mimetic or cyclic peptide mimetic conjugate as described. The foregoing and other objects, features, and advantages will become more apparent from the following detailed description, which proceeds with reference to the accompanying figures. The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fec. BRIEF DESCRIPTION OF THE DRAWINGS The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fec. FIGS. 1A-1D show representative fused PET-CT images at 1-day post-injection of 64Cu-conjugate 43 formulated in sucrose/NaCl 0.9% (9% v/v) into (1A) 44 day- and (1B) 72 day-old female 5×FAD mouse monitoring progression of Aβ pathology; (1C) 40 min post-injection of 11C-PIB into 95-day-old 5×FAD mouse; (1D) 44-day-old WT female mouse at 1-day post-injection of 64Cu-conjugate 43. Green and blue represent highest and zero uptake. Yellow arrow points to Aβ species accumulation in thalamus. A different intensity scale was used for PET images with 11C-PIB. White arrows show accumulation of 11C-PIB in plaque at the cortex. In (1B), co-registration of experimental image data with brain mask to identify mouse atlas space was achieved to identify volumes of interest (VOI). 1. Striatum; 2. Cor