These Protein Picker-Uppers Keep Your Cells Clean and Healthy

This story is part of a series on how we clean—from organizing your house to washing your tuchus.

Of all the existential intergalactic threats ever faced by the crew of the starship Enterprise, perhaps none burns more brightly in the minds of classic Star Trek fans than the gaping, antiproton-beam-backlit maw of the Planet Killer. What could be more memorable, after all, than a miles-long, barrel-shaped machine that prowls through space, inhaling planets through one end and chopping them into rubble to be expelled out the other? Now imagine a microscopic version of that and you’ve got yourself a proteasome, one of the most essential molecular machines inside the human body. Instead of breaking down planets though, it hacks apart proteins.

This tubular apparatus of orderly extermination is essentially a cellular garbage disposal, keeping thousands of damaged, misfolded, or otherwise obsolete proteins from piling up inside your cells like so much interplanetary space junk. Over the past two decades, as biochemists began figuring out how this natural trash-clearing system works, some discovered ways to trick it into terminating nearly any protein they wanted.

Today, investors are pouring billions of dollars into what many hope will be the next generation of blockbuster drugs based on programmable proteasomes. In the last few years, nearly every major pharmaceutical firm has begun negotiating deals with startups specializing in targeted protein degradation—as the rapidly expanding drug strategy is known—or spinning up their own internal development programs. Whereas small molecules like ibuprofen and benadryl gum up proteins, and Crispr knocks out the genes that make proteins, protein degraders offer a radical new way to selectively reach into cells and attack a whole host of historically difficult-to-treat diseases caused by misbehaving molecules, from Alzheimer’s to Parkinson’s to many types of cancer.

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At least, theoretically. The key is getting a protein of interest labeled for disposal. That’s the job of a special enzyme called a ubiquitin ligase; anything it slaps a chemical tag on gets hauled off to a proteasome and, poof, no more protein. Getting it to tag a specific protein is simply a matter of designing a molecule that can tether the ligase and the protein together. The idea’s been around since the late ’90s, but until recently, most demonstrations had taken place only in academic labs. That’s because most pharmaceutical companies assumed these proteasome-recruiting molecules, which are quite large and ungainly by drug standards, would never be able to slip across the membranes of intestinal cells and get into the bloodstream. In other words, the biology worked, but the chemistry was no good.

But a small Connecticut-based biotech company called Arvinas is changing that assumption. Founded in 2013 by Yale biochemist Craig Crews, one of the scientists who pioneered the now-patented protein disappearing act, Arvinas spent its first few years chemically tweaking its molecules to make them work inside the human body. In March, it began recruiting patients for the first-ever clinical trial of protein degraders. The company will test out the method on prostate cancer patients first, with another trial starting later this year for breast cancer. “The concept is incredibly compelling, but the big question has always been, can you get these large molecules to behave well?” says Tim Shannon, a partner at Canaan Partners and an early investor in Arvinas who served as its CEO until 2015. “That’s what we’re about to find out. Because if you can create one of these successfully, then you can do more.”

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