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Pharmaceuticals in joint-linker configurations for treating pathological blood clots

  • US 10,383,947 B2
  • Filed: 07/18/2016
  • Issued: 08/20/2019
  • Est. Priority Date: 01/16/2015
  • Status: Active Grant
First Claim
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1. A molecular construct comprising a first linker unit and a second linker unit, wherein,the first linker unit comprises,a first center core comprising a plurality of amine groups,a first linking arm linked to the first center core,a first element linked to the first linking arm, andoptionally, a first coupling arm linked to the first center core;

  • the second linker unit comprises,a second center core comprising a plurality of amine groups,a second linking arm linked to the second center core,a second element linked to the second linking arm, andoptionally, a second coupling arm linked to the second center core; and

    the first and second linker units are coupled to each other via copper catalyzed azide-alkyne cycloaddition (CuAAC) reaction, strained-promoted azide-alkyne click chemistry (SPAAC) reaction or inverse electron demand Diels-Alder (iEDDA) reaction occurred between any of the followings;

    the first and second center cores, the first coupling arm and the second center core, the first and second coupling arms, or the first center core and the second coupling arm;

    wherein,the first or second center core is independently a polypeptide core or a compound core, whereinthe polypeptide core comprises, (1) a plurality of lysine (K) residues, wherein each K residue and its next K residue are separated by a filler sequence comprising glycine (G) and serine (S) residues, and the number of K residues ranges from 2 to 15;

    or (2) the sequence of (Xaa-K)n, where Xaa is a PEGylated amino acid having 2 to 12 repeats of ethylene glycol (EG) unit, and n is an integer from 2 to 15;

    wherein at least one of the N- and C-terminal amino acid residues of the polypeptide is an amino acid having an azide or an alkyne group or is a cysteine residue, and when one of the N- and C-terminal amino acid residues is the cysteine residue, the linker unit further comprises, optionally, the coupling arm that is linked to the cysteine residue via the thiol group of the cysteine residue and has an azide, an alkyne, a tetrazine, a cyclooctene, or a cyclooctyne group at the free terminus thereof; and

    the compound core is selected from the group consisting of, benzene-1,3,5-triamine, 2-(aminomethyl)-2-methylpropane-1,3-diamine, tris(2-aminoethyl)amine, benzene-1,2,4,5-tetraamine, 3,3′

    ,5,5′

    -tetraamine-1,1′

    -biphenyl, tetrakis(2-aminoethyl)methane, tetrakis-(ethylamine)hydrazine, N,N,N′

    ,N′

    -tetrakis(aminoethyl)ethylenediamine, benzene-1,2,3,4,5,6-hexaamine, 1-N,1-N,3-N,3-N,5-N,5-N-hexakis(methylamine)-benzene-1,3,5-triamine, 1-N,1-N,2-N,2-N,4-N,4-N,5-N,5-N,-octakis(methylamine)-benzene-1,2,4,5-triamine, and N,N-bis[(1-amino-3,3-diaminoethyl)pentyl] methanediamine; and

    the first or second coupling arm linked to said compound core is linked thereto via forming an amide bond with one of the plurality of amine groups of the compound core and has an azide, an alkyne, a tetrazine, a cyclooctene, or a cyclooctyne group at the free-terminus thereof;

    the first and second linking arms are respectively linked to the amine groups of the first and second center cores via forming an amide bond;

    the first and second elements are respectively linked to the first and second linking arms via forming an amide bond, or via thiol-maleimide, CuAAC, iEDDA, or SPAAC reaction; and

    the first element is an scFv specific for fibrin, and the second element is a tissue plasminogen activator, an inhibitor of Factor Xa, or an inhibitor of thrombin.

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