Structure–activity Relationships of Amyloid Beta‐aggregation Inhibitors Based on Curcumin: Influence of Linker Length and Flexibility

Abstract

Self-assembly of amyloid beta into fibrillar plaques is characteristic of Alzheimer's disease and oligomers of this peptide are believed to be involved in neurodegeneration. Natural organic dyes, such as congo red and curcumin, bind tightly to amyloid beta and, at higher concentrations, block its self-assembly. The ability of these molecules to prevent amyloid accumulation has generated interest in understanding which of their structural features contribute to inhibitory potency. In general, amyloid beta ligands tend to be flat, planar molecules with substituted aromatic end groups; however, a comprehensive structure-activity study has not been reported. To better understand these ligands, we surveyed the effect of three prominent features on inhibition of amyloid aggregation: the presence of two aromatic end groups, the substitution pattern of these aromatics, and the length and flexibility of the linker region. We found that modification of any one of the modules has profound effects on activity. Further, we report that the optimal length of the linker lies within a surprisingly narrow regime (6-19 A). These results offer insight into the key chemical features required for inhibiting amyloid beta aggregation. In turn, these findings help define the nature of the docking site for small molecules on the amyloid beta surface.

Hopeahainol A attenuates memory deficits by targeting β‐amyloid in APP/PS1 transgenic mice

“…Therefore, prevention of Ab aggregation and attenuation of its neurotoxicity have been the focus of AD therapies. This study suggested that HopA might bind to Ab 1-42 directly through four negatively charged residues, Glu3, Asp7, Glu22, and Ala42, which was possibly due to its functional groups, such as the hydroxyl group, and aromatic rings (Reinke & Gestwicki, 2007). Clinical trials showed that immunization with Ab 42 could clear the amyloid plaques in patients with AD, but it did not prevent progressive neurodegeneration (Holmes et al, 2008).…”

“…Certain molecules, such as curcumin, are able to bind to Ab directly and inhibit its aggregation due to three key structural features -two phenolic end groups, the proper substitution pattern of these aromatic rings and the appropriate length and flexibility of the linker region (Reinke & Gestwicki, 2007;Parachikova et al, 2010). Hopeahainol A (HopA), with a molecular formula of C 28 H 16 O 8 , is a potentially acetylcholinesterase (AChE)-inhibitory and anti-oxidative polyphenol in H 2 O 2 -treated PC12 cells with a novel carbon skeleton isolated from Hopea hainanensis in our laboratory (Ge et al, 2008;Nicolaou et al, 2010).…”

Salvianic borneol ester reduces β-amyloid oligomers and prevents cytotoxicity

“…On the one hand, it was reported that some polyphenolic compounds preventing amyloid accumulation have two aromatic end groups and the length and flexibility of the linker region are related to inhibitory activity (Reinke Gestwicki, 2007). On the other hand, some nonsteroidal anti-inflammatory drugs (such as ibuprofen) that have an aromatic-based hydrophobic structure with some fused ring structures and methyl and/or carboxyl groups can also destabilize Aβ aggregates (Hirohata et al, 2008).…”

Small molecule inhibitors of Aβ‐aggregation and neurotoxicity

“…Indeed, curcumin and related compounds like calebin-A, dimethoxycurcumin, and bidemethoxycurcumin, inhibit fibril formation and extension and promote destabilization of pre-aggregated Ab peptides [Kim et al, 2005;Ono et al, 2004;Park and Kim, 2002;Yang et al, 2005]. Examination of the structure-activity function of curcumin has identified three important molecular features, including a hydroxyl substitution on the aromatic end group, a narrow linker length between 8-16 Å , and the presence of a second terminal phenyl group that determines its anti-aggregant properties [Reinke and Gestwicki, 2007]. In vitro, curcumin protects against Ab-induced death of PC-12, SH-SY5Y neuroblastoma, and human umbilical vein endothelial cells, via anti-oxidant actions [Baum and Ng, 2004;Kim et al, 2001;Park and Kim, 2002;Yang et al, 2005].…”

“…This demand implicates a very precise interaction that must occur between the negatively charged sulfonate groups and Ab for efficacy. Recently, three structural features have been discovered as necessary for an effective and potent inhibitor to Ab [Reinke and Gestwicki, 2007]. First, a second terminal phenyl group must be present in the inhibitor compound that interacts with Ab, as it is essential for activity.…”