TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore
Apr12

TEDMED and Alzheimer’s: Gregory Petsko, Reisa Sperling, and the next Al Gore

Gregory Petsko knows why he came to TEDMED. "I'm looking for Al Gore," he told me flat-out over lunch. Folks who know Petskoknow the former Brandeis University biochemistry department chair isn't one to mince words. And he's nailed the reason why an academic might want to look outside traditional conferences and soak up some of the TEDMED aura. He's looking for a charismatic champion to take up a biomedical cause: in Petsko's case, it's support for research in Alzheimer's disease. Petsko and Reisa Sperling, director of the Center for Alzheimer's Research and Treatment at Brigham and Women’s Hospital, talked about Alzheimer's at TEDMED on Wednesday. Both talks were cast as calls to action. Just consider the introduction Petsko got from TEDMED chair and Priceline.com founder Jay S. Walker: "This is a man who hears a bomb ticking." Alzheimer's statistics are sobering and Petsko used them to dramatic effect. People who will reach 80 by the year 2050 have a 1 in 3 chance of developing the disease if nothing is done, he told the audience. "And yet I hear no clamor," he said. "I hear no sense of urgency." Petsko shared some not-yet-published work with TEDMED's audience. His team is looking at a less-trod path of Alzheimer's biology-- the role protein sorting defects might play in the development of the disease. Their focus is on a protein complex called the retromer, which Petsko likened to a truck driver, because its job is to sort and send proteins either to the golgi--the cell's recycling center, or to the lysosome for snipping. For Alzheimer's, the thought is that improper sorting can make the difference between normalcy and an accumulation of amyloid-beta, the protein thought to be a key player in developing the disease. Petsko told me that his collaborator, Scott Small of Columbia University Medical School, discovered that retromer played a role in Alzheimer's (Neuron, DOI: 10.1016/j.neuron.2006.09.001).   Petsko's team has developed small molecules that increase the level of active retromer complex in the cell. So far, their agents have been evaluated in cultured cells. Tests in mice are ongoing. It's important for the Alzheimer's field to look beyond amyloid-beta, says Kevin Sweeney, a TEDMED attendee who teaches at the University of California, Berkeley's Haas School of Business and is part of the Rosenberg Alzheimer's Project, a nascent organization that supports alternative avenues in Alzheimer's research. "For a while, at least, the Alzheimer's space looks like so many of the [clinical] trials have pursued a relatively narrow range of theories," he says. Even though those theories aren't fully played out, "we still think it's useful to start looking for other strands,"...

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Alzheimer’s Meds from Plants: Satori Digs up New Leads
Jul20

Alzheimer’s Meds from Plants: Satori Digs up New Leads

Earlier this week, Satori Pharmaceuticals reported from the 2011 Alzheimer’s Association International Conference two new promising lead molecules, SPI-1802 and SPI-1810. Both block gamma-secretase, one of several enzymes involved in snipping the lengthy amyloid precursor protein down to beta-amyloid, the peptide that makes up the plaques coating the Alzheimer’s brain. A slew of big pharma companies are pursuing compounds that inhibit the enzyme (see here for more on the subject). So, you ask: What’s so new about Satori’s approach? For starters, Satori is trying to be very specific about what their compounds target. The researchers claim their compounds promote selective degradation of a single type of brain plaque – Amyloid β-42, the plaque most commonly associated with the disease – without destroying other, shorter amyloid residues (Aβ-38 and -40) that may actually confer neural health benefits. A Satori patent from June 2010 shows the selective amyloid-destroying  abilities are due to six-ring structures isolated from flowering plants. Who says new drugs aren’t discovered from natural products anymore? The patent literature dug up by our gang suggests that Satori’s leads come from the earth; specifically that they are semisynthetic derivatives of compounds extracted from the roots of black cohosh (snakeroot). Native American and Chinese herbal medicine use preparations of this plant, usually brewed as root teas, to aid muscle cramps and pain associated with menstruation or menopause.  Just a casual glance at Satori’s lead structure evokes phytosterol hallmarks: cyclopropanation at C9-C10 (a precursor to B-ring expansion in compounds like cortistatin A, a sea sponge isolate), a highly oxygenated terpene end chain, and a glycosidic linkage off of carbon 1 (far left), coupled to a typical plant sugar such as arabinose or xylose. A major critique of early Alzheimer’s drugs was that it wasn’t clear they were actually binding to their intended enzyme targets, which could explain some of their disappointing clinical results. Indeed, Eli Lilly this week provided more data confirming semagacestat, its lead gamma-secretase inhibitor, actually worsened rather than ameliorated patients’ conditions. Interestingly, Satori’s lead molecules look nothing like most of the big pharma compounds: Semagacestat is a peptide-linked lactam, while Merck’s lead molecules are iminopyrimidones with heterocycles stapled on. It's still too early to tell if the major structural differences in these new lead compounds will overcome the issues associated with semagacestat. But Satori scientists have one selling point: their compounds do not interfere with Notch, a protein involved in a host of key cell–signaling processes, including helping to control cell differentiation, proliferation, and cell death. It also happens to be a substrate for gamma-secretase. The challenge of blocking gamma secretase without disrupting Notch has caused many drug companies to...

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