Issue Date: June 27, 2011
Peptides Block Fibril Formation
Peptides designed to interact with a specific small fraction of an amyloid-forming protein can inhibit fibril formation by the intact protein as well, researchers at the University of California, Los Angeles, recently reported (Nature,DOI: 10.1038/nature10154).
David Eisenberg says his team’s study “validates the strategy” of looking for inhibitors of amyloid fibril formation by concentrating on a small portion of the protein. “At this point, there’s no way of determining atomic-level information for whole amyloid fibers,” such as those implicated in Alzheimer’s disease, type 2 diabetes, and other diseases, Eisenberg says. “This small, adhesive bit of six residues forms fibers, but they contain only six residues out of the hundreds in the whole protein.”
“It’s quite interesting that molecules designed to bind to crystallized fragments of amyloid-forming proteins can act as inhibitors of amyloid formation by the full-length proteins,” says Robert Tycko, an expert on amyloid structure at the National Institutes of Health. “This work shows that high-resolution structural information from amyloid-like microcrystals has direct relevance to the structures of amyloid fibrils themselves and may also have therapeutic relevance.”
To build the inhibitors, Eisenberg and his team started with a crystal structure of a six-amino acid segment of the much larger, fibril-forming tau protein, which is associated with Alzheimer’s. The segment, which is able to form fibrils on its own, is thought to be the portion that seeds the fiber formation of the full-length protein.
The crystal structure of this fragment, which Eisenberg and colleagues reported in 2007 (Nature,DOI: 10.1038/nature05695), shows that the fibril consists of a “steric zipper” in which each layer consists of two β strands with interdigitated amino acid side chains. Using the crystal structure as a template, the researchers computationally designed a hexapeptide that caps the fibril and blocks its elongation.
The inhibitor is made of nonnatural
Furthermore, the inhibitor is specific to the tau protein. For example, it doesn’t prevent fibril formation of amyloid-β, another amyloid-forming peptide associated with Alzheimer’s.
Such specificity is good “because there are functional amyloids in our bodies,” Eisenberg says. “If an inhibitor were completely general, it would have enormous side effects.”
In addition to the inhibitor for tau, Eisenberg and his team designed an inhibitor for another amyloid-forming protein, known as SEVI (semen-derived enhancer of viral infection), which greatly accelerates HIV infection. The inhibitor was able to block fibril formation and suppress HIV infection except at the highest concentrations of SEVI.
Eisenberg is quick to point out that neither of these inhibitors—especially the tau inhibitor—is a drug.
“Tau fibrillizes in cells in the brain. There’s no way that a peptide is likely to get into the brain and into cells,” Eisenberg says.
Warren J. Goux, a chemist at the University of Texas, Dallas, agrees. He studies tau tangles, and he has collaborated with Eisenberg in unpublished studies of the inhibitor.
“We found that the peptide could not get into neurons and, hence, was ineffective in the effort to rescue” neurons from tau fibrils, Goux says. “While the peptide appears to work well in vitro to inhibit amyloid formation of tau-related peptides, much work still needs to be done in order to make these effective therapeutic agents.
“Unfortunately, we find most agents that inhibit amyloid fibril formation, including many organic dyes, are also toxic to neurons,” Goux continues. “There seems to be a fine line between toxicity of the inhibitor and toxicity of the amyloid-forming sequence.”
Eisenberg sees more therapeutic potential for a peptide such as the SEVI inhibitor, which would not need to get into the brain or cells. “It could be some sort of vaginal foam or cream or spray,” he says.
But the most important aspect of the work is as a method of identifying new amyloid inhibitors, according to Steven O. Smith, director of the Center for Structural Biology at the State University of New York, Stony Brook. “The work describes a general path forward for the design of inhibitors targeting any amyloid-forming sequence of interest,” he says.
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