Small molecules that covalently modify transthyretin
AssigneeThe Scripps Research Institute
InventorsJeffery W. Kelly, Sungwook Choi
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Abstract
A family of covalent kinetic stabilizer compounds that selectively and covalently react with the prominent plasma protein transthyretin in preference to more than 4000 other human plasma proteins is disclosed. A contemplated compound corresponds in structure to Formula I, below, where the various substituents are defined within, and reacts chemoselectively with one or two of four Lys-15 ε-amino groups within the transthyretin tetramer. The crystal structure confirms the binding orientation of the compound substructure and the conjugating amide bond. A covalent transthyretin kinetic stabilizer exhibits superior amyloid inhibition potency, compared to a non-covalent counterpart, and inhibits cytotoxicity associated with amyloidogenesis.
Claims7
A method for assaying for the presence of transthyretin (TTR) in a sample to be assayed that comprises the steps of:
- a) admixing a binding/reaction sufficient amount of a covalent TTR kinetic stabilizer compound of Formula II with a sample to be assayed,
- wherein
- the depicted structure Ar is a hydrocarbyl aromatic ring structure,
- R1 is a halide, a methyl, monofluoro-, difluoro- or trifluoromethyl group;
- R2 is H, OH or NH2;
- n is one;
- L is a linker that is HC═CH;
- X is a reactive substituent that reacts with an amine in an aqueous environment to bond the amine to the depicted compound that is a carboxylic ester or thioester, an azetidin-2-one, a Michael acceptor, an epoxide, aziridine or thienyl group or a □-haloacetyl group, and L and X are in a 1,3-substitution relationship on the ring to which they are bonded;
- and
- Z is H, or a second linker, L2, that is an X group that is the same as or different from the previously mentioned X group, a NR3R4 group, where R3 and R4 are the same or different and are H, methyl or ethyl, a 1,3-diketo group or a metal ion chelating group;
- b) maintaining that admixture for a time period sufficient for said compound to bind to TTR present in the sample, react therewith and form a covalently-bound reacted compound, and
- c) determining the presence of said reacted compound.
Dependencies are inferred from the claim text.