&39Molecular Cap&39 May Help Prevent Alzheimer&39s HIV
A new advance by UCLA biochemists has brought scientists one step closer to developing treatments that could delay the onset of Alzheimer's disease and prevent the sexual transmission of HIV.
The researchers report that they have designed molecular inhibitors that target specific proteins associated with Alzheimer's disease and HIV to prevent them from forming amyloid fibers, the elongated chains of interlocking proteins that play a key role in more than two dozen degenerative and often fatal diseases.
"By studying the structures of two key proteins that form amyloids, we were able to identify the small chain of amino acids responsible for amyloid fiber formation and engineer a 'molecular cap' that attaches to the end of the fibers to inhibit their growth," said research leader David Eisenberg, director of the UCLA–Department of Energy Institute of Genomics and Proteomics and a Howard Hughes Medical Institute investigator.
The study was published online June 15 in the journal Nature and will be available in an upcoming print edition.
"This research is an important first step toward the development of structure-based drugs designed against amyloid diseases," said Eisenberg, who is a UCLA professor of chemistry, biochemistry and biological chemistry and a member of the California NanoSystems Institute at UCLA. "Our results have opened up an avenue so that universities and industry can start creating therapeutics that could not have been produced 10 years ago."
Toward delaying Alzheimer's disease
Amyloid fibers are elongated, water-tight structures formed from two linked protein sheets. Proteins from each sheet contribute side chains, causing them to interlock like the teeth of a zipper, Eisenberg said.
The fibers are found not only Alzheimer's disease but in a variety of conditions, including Lou Gehrig's disease, Parkinson's disease, type II diabetes and a family of disorders related to mad cow disease, among others. In Alzheimer's and other neurodegenerative diseases, the tau protein forms amyloid fibers inside brain cells, destroying them through a mechanism that is still being investigated.
Though many serious diseases are characterized by amyloid fibers, Alzheimer's is the most prevalent, Eisenberg said. Today there are 5 million patients in the U.S. who suffer from Alzheimer's, with 500,000 new cases every year. Alzheimer's health care cost this year alone have been estimated at $178 billion, including the value of unpaid care for Alzheimer's patients provided by nearly 10 million family members and friends.
"By the year 2050, it is projected that there will be 19 million Alzheimer's patients," Eisenberg said. "The care of so many patients with this debilitating illness could be a substantial fraction of the gross domestic product of the United States."
Eisenberg and his research team found that of the entire tau protein, a small chain of just six amino acids—abbreviated VQIVYK—was responsible for the formation of amyloid fibers. By studying the structure of the fibers using microcrystallography, a method developed at UCLA for this research, the team was able to use the fibers as a template to design an inhibitor that could 'cap' the fiber and stop it from growing.
The results were dramatic. The introduction of the inhibitor into a tau protein solution completely prevented amyloid fiber formation, validating the idea that the structure-based design of therapeutics for amyloid diseases is a plausible option.
Despite this success, there is still a long road ahead before a viable therapeutic can be developed to combat the onset of Alzheimer's in human patients, Eisenberg said. The inhibitor, a chain of amino acids, is far too large to penetrate deep into the brain where the tau proteins form amyloid fibers.
"This research is an important step toward identifying smaller molecules that can be utilized to develop a therapeutic," Eisenberg said. "Our goal is to be able to delay the onset of Alzheimer's disease."
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