Peptides capable of inhibiting protein-protein interactions at gabab1a subunit and uses thereof
AssigneesUniversity of Copenhagen, UniversitäT Basel
InventorsVita Sereikaite, Ziyang Chen, Pascal Rem, Bernhard Bettler, Kristian StrØmgaard
Life of this patent
Estimating the term…
Abstract
The present invention relates to peptides capable of inhibiting protein-protein interactions of GABABR1a receptors and uses thereof.
Claims65
A peptide comprising or consisting of the sequence 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
- (SEQ ID NO:
- 64)
- E X1 X2 X3 X4 X5 X6 W X7 X8 X9 X10 D X11 D
- wherein
- X1 is Aspartic acid (D) or Threonine (T),
- X2 is Aspartic acid (D) or Glutamic acid (E),
- X3 is S, Aspartic acid (D), Tyrosine (Y) or Phenylalanine (F),
- X4 is absent, Tryptophan (W), 3-(2-naphthyl)-L-alanine (2Nala), O-ethyl-L-tyrosine (Oetyr), O-benzyl-L-tyrosine (Obtyr), or L-Cysteic acid (Cya),
- X5 is Isoleucine (I) or Threonine (T),
- X6 is Aspartic acid (D), Tryptophan (W) or Alanine (A),
- X7 is Tyrosine (Y) or Glycine (G),
- X8 is Glycine (G), Proline (P) or Aspartic acid (D),
- X9 is Alanine (A), Threonine (T) or Serine(S),
- X10 is absent, Glycine (G), Serine(S) or Alanine (A),
- X11 is Aspartic acid (D), Threonine (T) or Glutamic acid (E),
- or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions
The peptide according to anyone of the preceding claims, wherein said peptide is an inhibitor of GB1a/2Rs (heterodimeric gamma-amino butyric acid (GABA)B1a/GABAB2 receptor).
The peptide according to anyone of the preceding claims, wherein said peptide is an inhibitor of protein-protein interactions at GB1a/2Rs.
The peptide according to anyone of the preceding claims, wherein X1 is D.
The peptide according to anyone of the preceding claims, wherein X2 is D.
The peptide according to anyone of the preceding claims, wherein X3 is S, D or Y, such as wherein X3 is D or Y, such as wherein X3 is D.
The peptide according to anyone of the preceding claims, wherein X4 is absent, W, 2-Nal, O-Ey-Y or Obtyr.
The peptide according to anyone of the preceding claims, wherein X4 is absent.
The peptide according to anyone of the preceding claims, wherein X4 is W, 2-Nal, O-Ey-Y or Obtyr, such as wherein X4 is W or 2-Nal.
The peptide according to anyone of the preceding claims, wherein X5 is I or T.
The peptide according to anyone of the preceding claims, wherein X6 is D.
The peptide according to anyone of the preceding claims, wherein X8 is P or D.
The peptide according to anyone of the preceding claims, wherein X9 is A or S, and wherein X10 is absent.
The peptide according to anyone of the preceding claims, wherein X9 is T and X10 is G, S.
The peptide according to anyone of the preceding claims, wherein X10 is G, S or absent, such as wherein X10 is G or S, such as wherein X10 is absent.
The peptide according to anyone of the preceding claims, wherein X10 is absent and wherein X11 is D or T, such as wherein X10 is absent and wherein X11 is D.
The peptide according to anyone of the preceding claims, wherein X11 is D or E and wherein X10 is G, S.
The peptide according to anyone of the preceding claims, wherein the peptide or functional variant thereof comprises at least 8 amino acid residues, such as 9 amino acid residues, such as 10 amino acid residues, such as 11 amino acid residues, such as 12 amino acid residues, such as 13 amino acid residues, such as 14 amino acid residues, such as 15 amino acid residues, such as 16 amino acid residues, such as 17 amino acid residues, such as 18 amino acid residues, such as 19 amino acid residues, such as 20 amino acid residues, such as 21 amino acid residues, such as 22 amino acid residues, such as 23 amino acid residues, such as 24 amino acid residues, such as 25 amino acid residues, such as 26 amino acid residues, such as 27 amino acid residues.
The peptide according to anyone of the preceding claims, wherein the peptide or functional variant thereof comprises between 8 and 35 amino acid residues, such as between 8 and 30 amino acid residues, such as between 8 and 27 amino acid residues, such as between 8 and 23 amino acid residues.
The peptide according to anyone of the preceding claims, wherein the peptide is selected from the group consisting of:
- SEQ ID NO:
- 15:
- TETEFIAWGPTGDED
- SEQ ID NO:
- 16:
- EDDDWIDWYDSDDD
- SEQ ID NO:
- 17:
- EDDDWIDWGPTSDDD
- SEQ ID NO:
- 18:
- EDDYIDWYDSDDD
- SEQ ID NO:
- 19:
- EDDYIDWGPTSDDD
- SEQ ID NO:
- 20:
- EDDD(2Nala)IDWYDSDDD
- SEQ ID NO:
- 21:
- EDDD(2Nala)IDWGPTSDDD
- SEQ ID NO:
- 22:
- EDDYTDWYDSDDD
- SEQ ID NO:
- 23:
- EDDYTDWGPTSDDD
- SEQ ID NO:
- 24:
- ETEFIAWGPTADED
- SEQ ID NO:
- 25:
- ETEYIAWGPTGDED
- SEQ ID NO:
- 26:
- ETEFIDWGPTGDED
- SEQ ID NO:
- 27:
- EDDSWIWWGPTGDED
- SEQ ID NO:
- 28:
- EDDSWIWWYGADTD
- SEQ ID NO:
- 29:
- EDDSWIDWGPTGDED
- SEQ ID NO:
- 30:
- EDDSWIDWYGADTD
- SEQ ID NO:
- 31:
- ETEFI(Cya)WGPTGDED
- SEQ ID NO:
- 32:
- EDDD(Oetyr)IDWYDSDDD
- SEQ ID NO:
- 33:
- EDDD(Obtyr)IDWYDSDDD
- SEQ ID NO:
- 34:
- EDDD(Oetyr)IDWGPTSDDD
- SEQ ID NO:
- 35:
- EDDD(Obtyr)IDWGPTSDDD
- or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions.
The peptide according to anyone of the preceding claims, wherein the peptide is N-terminally acetylated (Ac—N-terminus).
The peptide according to anyone of the preceding claims, wherein the peptide is C-terminally amidated (—NH2) or wherein the C-terminus is a carboxylic acid.
The peptide according to anyone of the preceding claims, wherein the peptide is conjugated to a cell-penetrating peptides (CPP).
The peptide according to anyone of the preceding claims, wherein the CPP is conjugated to the N-terminus or to the C-terminus of the peptide.
The peptide according to anyone of the preceding claims, wherein the CPP is conjugated to the peptide via a linker, such as via a peptidic linker.
The peptide according to anyone of the preceding claims, wherein the CPP is
- Tat,
- (SEQ ID NO:
- 55)
- YGRKKRRQRRR,
- R8,
- (SEQ ID NO:
- 56)
- RRRRRRRR,
- R7,
- (SEQ ID NO:
- 57)
- RRRRRRR,
- R6,
- (SEQ ID NO:
- 58)
- RRRRRR,
- R5,
- (SEQ ID NO:
- 59)
- RRRRR,
- R4,
- (SEQ ID NO:
- 60)
- RRRR,
- R3, RRR,
- or
- R2, RR.
The peptide according to anyone of the preceding claims, wherein the CPP is
- R8,
- (SEQ ID NO:
- 56)
- RRRRRRRR
- or
- R4,
- (SEQ ID NO:
- 60)
- RRRR.
The peptide according to anyone of the preceding claims, wherein the peptide is selected from the group consisting of:
- SEQ ID NO:
- 15:
- Ac-TETEFIAWGPTGDED-NH2
- SEQ ID NO:
- 16:
- Ac-EDDDWIDWYDSDDD-NH2
- SEQ ID NO:
- 17:
- Ac-EDDDWIDWGPTSDDD-NH2
- SEQ ID NO:
- 18:
- Ac-EDDYIDWYDSDDD-NH2
- SEQ ID NO:
- 19:
- Ac-EDDYIDWGPTSDDD-NH2
- SEQ ID NO:
- 20:
- Ac-EDDD(2Nala)IDWYDSDDD-NH2
- SEQ ID NO:
- 21:
- Ac-EDDD(2Nala)IDWGPTSDDD-NH2
- SEQ ID NO:
- 22:
- Ac-EDDYTDWYDSDDD-NH2
- SEQ ID NO:
- 23:
- Ac-EDDYTDWGPTSDDD-NH2
- SEQ ID NO:
- 24:
- Ac-ETEFIAWGPTADED-NH2
- SEQ ID NO:
- 25:
- Ac-ETEYIAWGPTGDED-NH2
- SEQ ID NO:
- 26:
- Ac-ETEFIDWGPTGDED-NH2
- SEQ ID NO:
- 27:
- Ac-EDDSWIWWGPTGDED-NH2
- SEQ ID NO:
- 28:
- Ac-EDDSWIWWYGADTD-NH2
- SEQ ID NO:
- 29:
- Ac-EDDSWIDWGPTGDED-NH2
- SEQ ID NO:
- 30:
- Ac-EDDSWIDWYGADTD-NH2
- SEQ ID NO:
- 31:
- Ac-ETEFI(Cya)WGPTGDED-NH2
- SEQ ID NO:
- 32:
- Ac-EDDD(Oetyr)IDWYDSDDD-NH2
- SEQ ID NO:
- 33:
- Ac-EDDD(Obtyr)IDWYDSDDD-NH2
- SEQ ID NO:
- 34:
- Ac-EDDD(Oetyr)IDWGPTSDDD-NH2
- SEQ ID NO:
- 35:
- Ac-EDDD(Obtyr)IDWGPTSDDD-NH2
- SEQ ID NO:
- 36:
- Ac-RRRRRRRREDDDWIDWYDSDDD-NH2
- SEQ ID NO:
- 37:
- Ac-RRRREDDDWIDWYDSDDD-NH2
- SEQ ID NO:
- 38:
- Ac-RRREDDDWIDWYDSDDD-NH2
- SEQ ID NO:
- 39:
- Ac-RRRRRRRREDDDWIDWGPTSDDD-NH2
- SEQ ID NO:
- 40:
- Ac-RRRREDDDWIDWGPTSDDD-NH2
- SEQ ID NO:
- 41:
- Ac-RRREDDDWIDWGPTSDDD-NH2
- SEQ ID NO:
- 42:
- Ac-RRRREDDD(2Nala)IDWYDSDDD-NH2
- SEQ ID NO:
- 43:
- Ac-RRRREDDD(2Nala)IDWGPTSDDD-NH2
- or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions.
The peptide according to anyone of the preceding claims, wherein the peptide is a cyclic polypeptide.
The peptide according to anyone of the preceding claims, wherein the peptide is “head-to-tail” cyclized.
The peptide according to anyone of the preceding claims, wherein the peptide is “side chain-to-side chain” cyclized.
The peptide according to anyone of the preceding claims, wherein the peptide is “tail-to-side chain” cyclized.
The peptide according to anyone of the preceding claims, wherein the peptide is “side chain-to-head” cyclized.
The peptide according to anyone of the preceding claims, wherein the peptide is back bone cyclized.
The peptide according to anyone of the preceding claims, wherein the N-terminal amino acid residue is linked to the C-terminal amino acid residue via a peptide bond.
The peptide according to anyone of the preceding claims, wherein the N-terminal amino acid residue is linked to the C-terminal amino acid residue via a non-peptide chemical linker.
The peptide according to anyone of the preceding claims, wherein the peptides further comprises:
- a. two cysteines linked via a non-peptide chemical linker;
- and/or
- b. a cysteine linked to the N-terminal amino acid residue of the peptide.
The peptide according to anyone of the preceding claims, wherein the peptide further comprises two cysteines.
The peptide according to anyone of the preceding claims, wherein the peptide further comprise a cysteine at the N-terminal.
The peptide according to anyone of the preceding claims, wherein the peptide further comprises a cysteine at the C-terminal.
The peptide according to anyone of the preceding claims, wherein the peptide further comprises a cysteine at the N-terminal and a cysteine at the C-terminal.
The peptide according to anyone of the preceding claims, wherein a linker connects two cysteines within the peptide of the present disclosure.
The peptide according to anyone of the preceding claims, wherein a linker connects a cysteine at the N-terminal amino acid residue and a cysteine at the C-terminal amino acid residue of the peptide.
The peptide according to anyone of the preceding claims, wherein the non-peptide chemical linker is:
The peptide according to anyone of the preceding claims, wherein the peptide is selected from the group consisting of:
The peptide according to anyone of the preceding claims, wherein the peptide is
The peptide according to anyone of the preceding claims, wherein the peptide is
The peptide according to anyone of the preceding claims, wherein the peptide is
The peptide according to anyone of the preceding claims, wherein the peptide is
The peptide according to anyone of the preceding claims, wherein the peptide is
The peptide according to anyone of the preceding claims, wherein the peptide is
The peptide according to anyone of the preceding claims, wherein the peptide is conjugated to an additional moiety.
The peptide according to anyone of the preceding claims, wherein the peptide has binding affinity (Ki) to sushi domain (SD1/2) protein of 20 nM or less.
The peptide according to anyone of the preceding claims, wherein the peptide has membrane permeability (CP50) of 30 μM or less, such as of 10 μM or less.
The peptide according to anyone of the preceding claims, wherein the peptide has plasma stability (T1/2) of 12 hours or more, such as of 16 hours or more, such as of 20 hours or more, such as of 24 hours or more, such as of 30 hours or more, such as of 36 hours or more, such as of 40 hours or more, such as of 48 hours or more.
The peptide according to anyone of the preceding claims, wherein the peptide is capable of inhibiting an interaction between a protein and a sushi domain (SD) of GB1a at presynaptic neurons.
The peptide according to anyone of the preceding claims, wherein the peptide is capable of inhibiting an interaction between:
- sushi domain (SD) and adherence-junction associated protein 1 (AJAP1),
- SD and PILRα-associated neural protein (PIANP), and/or
- SD and amyloid precursor protein (APP).
A peptide according to anyone of the preceding claims for use as a medicament.
A peptide according to anyone of the preceding claims for use in the treatment of neurological and/or psychiatric disorders.
A peptide for use according to anyone of the preceding claims, wherein the neurological disorder is epilepsy, spasticity, schizophrenia, dystonia, neuropathic pain, narcolepsy, spasticity, cognitive deficits such as Mild cognitive impairment (MCI), autism spectrum disorder and/or substance-use disorders.
A peptide for use according to anyone of the preceding claims, wherein the psychiatric disorder is depression, anxiety and/or Attention deficit hyperactivity disorder (ADHD).
A method for treatment of neurological and/or psychiatric disorders comprising administration of a peptide according to anyone of the preceding claims to an individual in need thereof.
Use of a peptide according to anyone of the preceding claims for the manufacture of a medicament for the treatment of neurological and/or psychiatric disorders.
A medicament for use in the treatment or prevention of neurological and/or psychiatric disorders comprising a peptide according to anyone of the preceding claims.
Dependencies are inferred from the claim text.