A new approach to detoxifying the amyloid-β (Aβ) peptide borrows from an unlikely source—the field of cancer drugs. In the May 7 PNAS online, Kevin Barnham, Roberto Cappai, and colleagues from the University of Melbourne, Australia, report on a new class of platinum-based inhibitors of Aβ aggregation and toxicity.
The inhibitors are designed to target the high-affinity metal binding site of Aβ, where the presence of copper or zinc can contribute to Aβ’s damaging effects. While questions will need to be addressed about the specificity and safety of these particular compounds, the results present a novel approach to interfering with Aβ via blocking the residues responsible for metal binding.
For some time, the Australian researchers have been interested in inhibiting the interaction between Aβ and metals as a therapeutic strategy. That work resulted in the clinical testing of the metal chelator clioquinol in AD patients. After promising early results (see ARF related live discussion and ARF related news story), clioquinol was discontinued, but the second-generation drug PBT2 is still in the running (see ARF related drug story).
In the new work, Barnham and coworkers take a different tack. Rather than trying to tie up the metal, they target Aβ itself with the goal of blocking its metal-binding site with platinum. To do that, the investigators replaced two small amine groups that complex the platinum in the widely used cancer drug cisplatin with a polyaromatic phenanthroline structure. This scaffold is related to other Aβ binders including PIB, Congo red and thioflavin T, and contacts aromatic residues in the N-terminal region of Aβ42 near the metal-coordinating histidine side chains.
Structural studies using three versions of phenanthroline-platinum complex indicate that the new compounds bind to Aβ in vitro and alter its structure. Mass spectrometry and NMR pointed to platinum coordinating with the metal-binding histidine residues 6, 13, and 14. Circular dichroism measures suggested that the compounds prevented Aβ from adopting a β-sheet structure in the presence of copper.
The compounds affected Aβ toxicity as well. First, the platinum complexes inhibited two in-vitro correlates of Aβ toxicity, the time-dependent aggregation of Aβ42 and copper-mediated H2O2 production. The compounds were as potent at blocking peroxide production as clioquinol. Next, the researchers showed that the compounds prevented Aβ toxicity in mouse primary neuronal cultures, and one of the compounds was also shown to reverse the synaptic effects of Aβ on long-term potentiation in mouse hippocampal slices.
“The results from this work have given us the confidence that if we can design compounds that can get to the target in vivo, then we can reasonably expect that they are capable of inhibiting the deleterious effects of Aβ,” Barnham wrote to ARF in an e-mail. However, he continued, “The compounds described in the paper are unlikely to have the necessary properties to achieve this, so we have undertaken a chemistry program to design molecules capable of being orally administered and inhibiting Aβ in vivo. This work is ongoing and we have been able to synthesize Pt-based novel chemical entities and have begun studies in transgenic animals. Our initial studies have given us cause for optimism as we have seen changes in Alzheimer disease-related biomarkers such as Aβ oligomers and tau phosphorylation.”
The new compounds, Barnham wrote, have been patented and assigned to Prana Biotechnology Ltd. of Parkville, Victoria, Australia, the company that tested clioquinol and is developing PBT2. Barnham, Cappai, and their coauthors Ashley Bush, Colin Masters, and Robert Cherny are all disclosed on the PNAS paper as consultants to Prana.—Pat McCaffrey
- Barnham KJ, Kenche VB, Ciccotosto GD, Smith DP, Tew DJ, Liu X, Perez K, Cranston GA, Johanssen TJ, Volitakis I, Bush AI, Masters CL, White AR, Smith JP, Cherny RA, Cappai R. Platinum-based inhibitors of amyloid-beta as therapeutic agents for Alzheimer's disease. Proc Natl Acad Sci U S A. 2008 May 13;105(19):6813-8. PubMed.