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Harnessing Helices

Harnessing Helices - Harnessing Helices Chemical braces...

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Harnessing Helices Chemical braces hold peptides in place, heralding a potential new class of therapeutics Carmen Drahl TECHNOLOGY  for reinforcing the  α -helix, a familiar protein motif  throughout biology, could lead to a new class of peptide-based drugs.  Because of their particular blend of chemical properties, stabilized helices  may work against disease targets that have traditionally been out of reach. Courtesy of Shibani Bhattacharya FACE TO FACE A stabilized α-helix (pink) binds to a key portion of the HIV capsid (blue), as shown in an NMR structure. A hydrocarbon side-chain cross-link (yellow) helps this helix enter cells. Protein-embedded  α -helices mediate key protein handshakes in cancer,  HIV, and other diseases. But actually using an  α -helix as a drug has proven  tricky. So-called stapled  α -helices, boasting sturdy cross-links between  nonnatural amino acid side chains, just might change that. This class of  stabilized peptides can regulate signaling pathways to subvert cancer. They  also appear to overcome several of the usual problems that have hampered  the development of peptide drugs. The technology has reached the point  where a start-up company based on peptide-stapling technology is looking  ahead to the clinic. Meanwhile, basic research is ongoing to unravel some  of the biology behind how these strapped-down helices work and what  else they might be capable of doing. Gregory L. Verdine  is spearheading those research efforts. The Harvard  University chemical biologist pioneered the development of stapled  peptides and is the founder of  Aileron Therapeutics , the Cambridge,  Mass.-based start-up company working to develop stapled-peptide drugs. In Verdine's eyes, traditional small-molecule and protein drugs have  drawbacks that stapled peptides might address. For instance, he says, most  antibodies and protein therapeutics can be used only to target proteins on  the cell's outer surface. Stapled peptides can enter cells and therefore can  address protein-protein interactions inside cells, which for the most part  haven't been accessible with protein drugs.
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IN ADDITION,  because of their larger surface area relative to small  molecules, stapled helices can make contacts with other proteins over a  large, relatively flat surface area. This is how many protein-protein  interactions take place. In contrast, small molecules tend to bind best to  well-defined pockets on protein targets. "So many proteins have been disease targets for years, but they've been 
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Harnessing Helices - Harnessing Helices Chemical braces...

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