Ligand electronic properties modulate tau filament binding site density.
Small molecules that bind tau-bearing neurofibrillary lesions are being sought for premortem diagnosis, staging, and treatment of Alzheimer's disease and other tauopathic neurodegenerative diseases. The utility of these agents will depend on both their binding affinity and binding site density (B(max)). Previously we identified polarizability as a descriptor of protein aggregate binding affinity. To examine its contribution to binding site density, we investigated the ability of two closely related benzothiazole derivatives ((E)-2-[[4-(dimethylamino)phenyl]azo]-6-methoxybenzothiazole) and ((E)-2-[2-[4-(dimethylamino)phenyl]ethenyl]-6-methoxybenzothiazole) that differed in polarizability to displace probes of high (Thioflavin S) and low (radiolabeled (E,E)-1-iodo-2,5-bis(3-hydroxycarbonyl-4-methoxy)styrylbenzene; IMSB) density sites. Consistent with their site densities, Thioflavin S completely displaced radiolabeled IMSB, but IMSB was incapable of displacing Thioflavin S. Although both benzothiazoles displaced the low B(max) IMSB probe, only the highly polarizable analog displaced near saturating concentrations of the Thioflavin S probe. Quantum calculations showed that high polarizability reflected extensive pi-electron delocalization fostered by the presence of electron donating and accepting groups. These data suggest that electron delocalization promotes ligand binding at a subset of sites on tau aggregates that are present at high density, and that optimizing this aspect of ligand structure can yield tau-directed agents with superior diagnostic and therapeutic performance.
Department of Molecular and Cellular Biochemistry, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
Katryna
K
Cisek
Jordan R
JR
Jensen
Nicolette S
NS
Honson
Kelsey N
KN
Schafer
Grace L
GL
Cooper
Jeff
J
Kuret
D052160:Benzothiazoles / Q000737:chemistry*; D001665:Binding Sites; D004583:Electrons; D005456:Fluorescent Dyes / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D011789:Quantum Theory; D011994:Recombinant Proteins / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry*; D016875:tau Proteins / Q000737:chemistry*
D052160:Benzothiazoles; D005456:Fluorescent Dyes; D008024:Ligands; D011994:Recombinant Proteins; D013844:Thiazoles; D016875:tau Proteins; C009462:thioflavin T