Structural determinants of Tau aggregation inhibitor potency.
Small-molecule Tau aggregation inhibitors are under investigation as potential therapeutic agents against Alzheimer disease. Many such inhibitors have been identified in vitro, but their potency-driving features, and their molecular targets in the Tau aggregation pathway, have resisted identification. Previously we proposed ligand polarizability, a measure of electron delocalization, as a candidate descriptor of inhibitor potency. Here we tested this hypothesis by correlating the ground state polarizabilities of cyanine, phenothiazine, and arylmethine derivatives calculated using ab initio quantum methods with inhibitory potency values determined in the presence of octadecyl sulfate inducer under reducing conditions. A series of rhodanine analogs was analyzed as well using potency values disclosed in the literature. Results showed that polarizability and inhibitory potency directly correlated within all four series. To identify putative binding targets, representative members of the four chemotypes were added to aggregation reactions, where they were found to stabilize soluble, but SDS-resistant Tau species at the expense of filamentous aggregates. Using SDS resistance as a secondary assay, and a library of Tau deletion and missense mutants as targets, interaction with cyanine was localized to the microtubule binding repeat region. Moreover, the SDS-resistant phenotype was completely dependent on the presence of octadecyl sulfate inducer, but not intact PHF6/PH6* hexapeptide motifs, indicating that cyanine interacted with a species in the aggregation pathway prior to nucleus formation. Together the data suggest that flat, highly polarizable ligands inhibit Tau aggregation by interacting with folded species in the aggregation pathway and driving their assembly into soluble but highly stable Tau oligomers.
From the Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210.
Kelsey N
KN
Schafer
From the Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210.
Katryna
K
Cisek
From the Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210.
Carol J
CJ
Huseby
From the Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210.
Edward
E
Chang
From the Department of Molecular and Cellular Biochemistry, College of Medicine, The Ohio State University, Columbus, Ohio 43210. Electronic address: kuret.3@osu.edu.
Jeff
J
Kuret
D006801:Humans; D020125:Mutation, Missense; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000737:chemistry*; D017384:Sequence Deletion; D012967:Sodium Dodecyl Sulfate / Q000737:chemistry*; D012995:Solubility; D016875:tau Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C054369:MAPT protein, human; D016875:tau Proteins; D012967:Sodium Dodecyl Sulfate; D012236:Rhodanine
Aggregation; Alzheimer Disease; Chemical biology; Protein Structure; Tau