Insights into the Impact of a Membrane-Anchoring Moiety on the Biological Activities of Bivalent Compounds As Potential Neuroprotectants for Alzheimer’s Disease

Bivalent
compounds anchoring in different manners to the membrane
were designed and biologically characterized to understand the contribution
of the anchor moiety to their biological activity as neuroprotectants
for Alzheimer’s disease. Our results established that the anchor
moiety is essential, and we identified a preference for diosgenin,
as evidenced by 17MD. Studies in primary neurons and
mouse brain mitochondria also identified 17MD as exhibiting
activity on neuritic outgrowth and the state 3 oxidative rate of glutamate
while preserving the coupling capacity of the mitochondria. Significantly,
our studies demonstrated that the integrated bivalent structure is
essential to the observed biological activities. Further studies employing
bivalent compounds as probes in a model membrane also revealed the
influence of the anchor moiety on how they interact with the membrane.
Collectively, our results suggest diosgenin to be an optimal anchor
moiety, providing bivalent compounds with promising pharmacology that
have potential applications for Alzheimer’s disease.