Sandbox Reserved 1105: Difference between revisions
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== Disease == | == Disease == | ||
==Type of disease== | |||
The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. doi: 10.1039/c4cp04549a. PMID:25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> ARTICLE Human brain amyloidoses</ref> | The most known defect related to TTR is the formation of amyloid fibrils, which can engender several diseases such as familial amyloid polyneuropathy (FAP), familial amyloid cardiomyopathy (FAC), and senile systemic amyloidosis (SSA) also called wild-type transthyretin amyloid (WTTA or ATTR)<ref> Faria TQ, Almeida ZL, Cruz PF, Jesus CS, Castanheira P, Brito RM. A look into amyloid formation by transthyretin: aggregation pathway and a novel kinetic model. Phys Chem Chem Phys. 2015 Mar 4;17(11):7255-63. doi: 10.1039/c4cp04549a. PMID:25694367 doi:http://dx.doi.org/10.1039/c4cp04549a </ref>. Another type of disease possibly engendered due to TTR amyloid fibrils is the central nervous system selective amyloidosis (CNSA) including familial oculoleptomeningeal amyloidosis characterized by an eye injury, or meningocerebrovascular amyloidosis if the eye is not affected. <ref> ARTICLE Human brain amyloidoses</ref> | ||
===TTR amyloid fibril=== | |||
Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="RD"> Article RATIONAL DESIGN</ref> | Inappropriate TTR foldings cause amyloidosis. Indeed, aggregates formation can be explained by a destabilization of the TTR’s native conformation, namely the tetramer dissociation into an alternative folded monomeric intermediate. The final result is a protein self-assembly. A particular beta-pleated-sheet structure characterizes the proteins with amyloidogenic potential. <ref name="RD"> Article RATIONAL DESIGN</ref> | ||
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==Drug development== | |||
=== First drugs developed: Non-steroidal anti-inflammatory drugs=== | |||
Drug research is basée on the inhibition of amyloidogenic TTR by stabilization of native tetrameric conformation, using binding ligands to prevent TTR dissociation. | Drug research is basée on the inhibition of amyloidogenic TTR by stabilization of native tetrameric conformation, using binding ligands to prevent TTR dissociation. | ||
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== | === Dibenzofuran-4,6-dicarboxylic acid === | ||
<Structure load='1dvu' size='340' frame='true' align='right' caption='Crystal Structure of human transthyretin in complex with dibenzofuran-4,6-dicarboxylic acid from homo sapiens gene in Escherichia coli [[resolution 2.05Å]] (PDB entry : [[1dvu]]) ' scene='Insert optional scene name here' /> | <Structure load='1dvu' size='340' frame='true' align='right' caption='Crystal Structure of human transthyretin in complex with dibenzofuran-4,6-dicarboxylic acid from homo sapiens gene in Escherichia coli [[resolution 2.05Å]] (PDB entry : [[1dvu]]) ' scene='Insert optional scene name here' /> | ||
