Stabilized minimal coiled-coil mimetics

Patent metadata

Field	Value
Publication number	US-11440938-B2
Application number	US-202017003686-A
Country	US
Kind code	B2
Filing date	Aug 26, 2020
Priority date	Jun 8, 2015
Publication date	Sep 13, 2022
Grant date	Sep 13, 2022

Abstract

This invention relates to a macrostructure that includes an antiparallel coiled-coil structure or a parallel coiled-coil structure.

First claim

What is claimed is:

1. A macrostructure comprising:
(i) an antiparallel coiled-coil structure of FIG. 14
wherein:
each ∘ and each ⊗ is independently absent or a modified or unmodified amino acid residue or analogue thereof, with the proviso that at least seven contiguous amino acid residues/analogues are present in each coil, wherein
a, b, c, d, e, f, g, a′, b′, c′, d′, e′, f′, and g′ indicate the location of the amino acid residues/analogues within the coiled-coil structure and

each ⊗ amino acid residue is a modified or unmodified amino acid selected from the group consisting of cysteine, homocysteine, selenocysteine, leucine, isoleucine, hexafluoroleucine, valine, hexafluorovaline, allylglycine, threonine, and analogues of each of the preceding residues;
each is absent or a covalent linker (Linker) between two amino acid residues/analogues, wherein:
each Linker A is independently a linker between a g* amino acid residue and a g′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the g* amino acid residue and the Cα position of the g′* amino acid residue is 10-25 Å;
each Linker B is independently a linker between an a* amino acid residue and a d′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the a* amino acid residue and the Cα position of the d′* amino acid residue is 5-15 Å;
each Linker C is independently a linker between a d* amino acid residue and an a′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the d* amino acid residue and the Cα position of the a′* amino acid residue is 5-15 Å;
each Linker D is independently a linker between an e* amino acid residue and an e′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the e* amino acid residue and the Cα position of the e′* amino acid residue is 10-25 Å;
and

at least one Linker A or Linker D is present;

each is a point of attachment from a terminal nitrogen to H, —PG 1 , —C(O)R, —C(O)NR 2 , —C(O)NH 2 , —R, —C(O)OR, an amino acid, a peptide, a tag, or a targeting moiety, where each R is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an arylalkyl, a peptide, a targeting moiety, or a tag; and wherein PG 1 is a protecting group for protection of an amine; and
each is a point of attachment from a terminal carbonyl to H, —OPG 2 , —NPG 2 , —OR, —OH, —NR 2 , —NH 2 , —NRC(O)C 1-6 alkyl, —NHC(O)C 1-6 alkyl, an amino acid, a peptide, a tag, or a targeting moiety, where each R is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an arylalkyl, a peptide, a targeting moiety, or a tag; and wherein PG 2 is a protecting group for protection of a carboxylic acid;
or (ii) a parallel coiled-coil structure of FIG. 15
wherein:
each ∘ and each ◯ is independently absent or a modified or unmodified amino acid residue or analogue thereof, with the proviso that at least seven contiguous amino acid residues/analogues are present in each coil, wherein
a, b, c, d, e, f, g, a′, b′, c′, d′, e′, f′, and g′ indicate the location of the amino acid residues/analogues within the coiled-coil structure and
each ⊗ amino acid residue is a modified or unmodified amino acid selected from the group consisting of cysteine, homocysteine, selenocysteine, leucine, isoleucine, hexafluoroleucine, valine, hexafluorovaline, allylglycine, threonine, and analogues of each of the preceding residues;

each is absent or a covalent linker (Linker) between two amino acid residues/analogues, wherein:
each Linker E is independently a linker between a g* amino acid residue and an e′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the g* amino acid residue and the Cα position of the e′* amino acid residue is 10-25 Å;
each Linker F is independently a linker between a d* amino acid residue and a d′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the d* amino acid residue and the Cα position of the d′* amino acid residue is 5-15 Å;
each Linker G is independently a linker between an a* amino acid residue and an a′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the a* amino acid residue and the Cα position of the a′* amino acid residue is 5-15 Å;
each Linker H is independently a linker between an e* amino acid residue and a g′* amino acid residue, wherein the length of the linker is such that the spatial distance between the Cα position of the e* amino acid residue and the Cα position of the g′* amino acid residue is 10-25 Å; and
at least one Linker E or Linker H is present; and

each is a point of attachment from a terminal nitrogen to H, —PG 1 , —C(O)R, —C(O)NR 2 , —C(O)NH 2 , —R, —C(O)OR, an amino acid, a peptide, a tag, or a targeting moiety, where each R is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an arylalkyl, a peptide, a targeting moiety, or a tag; and wherein PG 1 is a protecting group for protection of an amine; and
each is a point of attachment from a terminal carbonyl to H, —OPG 2 , —NPG 2 , —OR, —OH, —NR 2 , —NH 2 , —NRC(O)C 1-6 alkyl, —NHC(O)C 1-6 alkyl, an amino acid, a peptide, a tag, or a targeting moiety, where each R is independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, a heteroaryl, a heterocyclyl, an arylalkyl, a peptide, a targeting moiety, or a tag; and wherein PG 2 is a protecting group for protection of a carboxylic acid.

2. The macrostructure of claim 1 , wherein each Linker is independently selected from the group, consisting of alkylene, alkenylene, arylene, heteroarylene, ethers, thioethers, amides, maleimides, esters, disulfides, diselenides, —O—, —S—, —Se—, and any combination thereof.

3. The macrostructure of claim 2 , wherein at least one of Linker A, Linker D, Linker E, and Linker H has the formula —Z n —, wherein n is a number from 1 to 25 and each Z is independently selected at each occurrence thereof from the group consisting of alkylene, alkenylene, arylene, heteroarylene, triazole-diyl, thiazole-diyl, oxazole-diyl, ethers, amides, esters, maleimides, thioethers, O, S, and Se.

4. The macrostructure of claim 3 , wherein the at least one of Linker A, Linker D, Linker E, and Linker H is independently selected from the group consisting of

wherein each marks a connection point to the Cα carbon in a linked residue/analogue.

5. The macrostructure of claim 3 , wherein the at least one of Linker A, Linker D, Linker E, and Linker H:
(i) has the formula

wherein:
Q 1 is a C 1-8 alkylene or a moiety of formula (C 1-8 alkylene-X—C 0-8 alkylene) n ;
Q 2 is C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, monocyclic carbocycle, fused bicyclic carbocycle, non-aromatic heterocycle, arylene, and heteroarylene, a moiety of formula C 1-8 alkylene-X—C 1-8 alkylene, or a moiety of formula -Q 4 -Q 5 -Q 6 -; wherein each C 1-8 alkylene, C 2-8 alkenylene, C 2-8 alkynylene, monocyclic carbocycle, fused bicyclic carbocycle, non-aromatic heterocycle, arylene, and heteroarylene can be optionally substituted from 1 to 4 (1, 2, 3, or 4) times with substituents independently selected at each occurrence thereof from the group consisting of H, halogen, C 1-8 alk

Assignees

• Univ New York

Inventors

• Arora Paramjit S
• Wuo Michael G

Classifications

• C07K14/00

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof · CPC title

• A61P35/02

  specific for leukemia · CPC title

• G01N33/68

  involving proteins, peptides or amino acids {(involving lipoproteins G01N33/92)} · CPC title

• C07K2319/73

  containing coiled-coiled motif (leucine zippers) · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title