Synthetic Peptides Spur Apoptosis

A PEPTIDE STAPLED: © 2004 AAAS To enhance helicity, protease resistance, and serum stability of BID BH3 peptide, researchers added a, a-disubstituted non-natural amino acids containing olefinic side chains. The substitutions were made to flank three amino acids when placed at position i and i+4, or six amino acids when placed at i and i+7 amino acids, so that reactive olefinic residues would reside on the same face of the a helix. (L.D. Walensky et al., Science, 305:1466–70, 2004.) Peptide mimetics are becoming increasingly popular pipeline leads for pro-apoptotic cancer drugs. They represent an intriguing way to gain entry to the complex cascades of protein-protein interactions in the cell-death pathway. This is because they can theoretically retain structural and functional properties of native apoptotic proteins, while being small enough to be easily synthesized. Natural peptides are generally not an option. "Peptides are essentially useless as therapeutic agents," says Gregory Verdine, professor of chemistry at Harvard University. Such peptides poorly penetrate cell membranes, are easily degraded by proteases in vivo, and tend not to fold into active conformations. Two recent studies demonstrate that some of these challenges can be overcome by adding nonnatural components to peptide chains. "We have all this specificity of protein-protein interactions, but we have not been able to take advantage of it," says Steven Dowdy, a Howard Hughes Medical Institute investigator at the University of California, San Diego. "Now, here are two different ways to take advantage of protein-protein interactions that lead to cell death." The approaches therefore provide a platform for the future development of therapeutics based on modifying signaling pathways. MIMICKING INTERACTIONS "We aimed to jump start the cell death process in cancer cells by inhibiting survival proteins and activating prodeath proteins." says Loren Walensky of the Dana-Farber Cancer Institute in Boston and lead author of one of the studies. To do this, Walensky and colleagues began with a peptide corresponding to the BCL-2 homology 3 (BH3) interaction domain, which is critical for inducing mitochondrial-dependent apoptosis. This peptide normally lacks an appropriate α-helical structure, but by placing α, α-disubstituted nonnatural olefinic amino acids within the peptide, they could bind it to a hydrocarbon chain.1 This essentially "staples" the peptide into an α-helix. Thus the attached BH3 peptide, termed a stabilized α-helix of BCL2 domain (SAHB), is more resistant to degradation, crosses the cell membrane, and kills leukemia cells, presumably through the activation of mitochondrial-dependent apoptosis. Furthermore, giving SAHB intravenously to mice bearing human leukemia-cell xenographs extended their median survival from five days to eleven. "This is very elegant and may turn out to have applicability to other α-helical peptides," says Dowdy. In a complementary study, Patrick Harran, lead author Lin Li, and their colleagues, from the University of Texas Southwestern in Dallas, took a different approach to the same idea, in this case making use of the interaction domain of the second mitochondria-derived activator of caspases (SMAC), an activator of apoptosis. With knowledge of the structure and biochemistry of SMAC, they could replicate its function with a small molecule, says Harran. Harran and colleagues synthesized a 180-member library of SMAC interaction peptides with their C-terminals replaced by non-peptidyl compounds. They ultimately found a small molecule, compound 3, which mimics SMAC's interaction with the integrin-associated protein (IAP).2 Normally this interaction induces apoptosis, and indeed, compound 3, in combination with other factors, caused tumor cells to undergo apoptosis, while sparing normal cells. "This reinforces the notion that the apoptotic pathway is an exciting target in cancer cells, with multiple sites of intervention," says Verdine a coauthor on the BH3 study. BUILDING ON THE PLATFORM " [The studies] are a nice technical demonstration that this type of strategy, involving chemical modification, could be made to work," says Anthony Letai, assistant professor at Harvard Medical School. In addition, both molecules provide excellent new reagents to tease apart how these protein-protein interactions function in vitro, he adds. Ziwei Huang, a professor from the Burnham Institute, La Jolla, Calif., says the studies provide a nice demonstration of the value of using small molecules to study the apoptotic pathway. "The two different approaches seem quite promising to a very active field," says Huang, although many challenges await the testing of these compounds in clinical trials, he adds. Nevertheless, the approach is drawing attention. Recently, Shaomeng Wang and colleagues at the University of Michigan used computational modeling to design new SMAC peptide mimetics.3 These compounds bind IAP 24 times stronger, and Wang and colleagues hope to also use them to kill cancer cells. Verdine says he believes such strategies can fill a hole in what is currently available for therapeutic use. "If the strategies hold out, they fit into the space between small synthetic molecules and biologicals ... which would fill a real void in pharmacologic targeting."

Synthetic Peptides Spur Apoptosis

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David Secko

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February 2005

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