The Marriage of Small Molecules and Biologics - Pharmaceutical Technology

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The Marriage of Small Molecules and Biologics
Approaches in using small-molecule and peptide synthesis offer promise in widening the scope of drug candidates.

Pharmaceutical Technology
Volume 35, Issue 5, pp. 56-60

In 2008, Aileron acquired exclusive rights from New York University for additional methods to stabilize peptides and peptidomimetics. In 2009, Aileron received $40 million in venture capital funding, which included funding from four pharmaceutical venture-capital funds: SR One (GlaxoSmithKline's venture capital fund), the Novartis Venture Fund, Lilly Ventures (Eli Lilly's venture capital fund), and the Roche Venture Fund.

Verdine recently spoke at the American Chemical Society's (ACS) National Meeting & Exposition in Anaheim, California, in late March 2011, to provide an update of his research at Harvard with respect to stapled peptides. "Our stapled peptides can overcome the shortcomings of drugs of the past and target proteins in the body that were once thought to be undruggable," he said in a Mar. 28, 2011, ACS press release. "They are a genuinely new frontier in medicine."

Verdine highlighted two stapled-peptide drug candidates that respectively target colon cancer and asthma. The colon-cancer stapled peptides inhibit activity of the protein β-catenin, which when present in a hyperactive form, causes cell to grow in an uncontrolled way. This protein has been linked with an increased risk of colon cancer and other types of cancer, including skin, brain, and ovarian cancer. When introduced to human colon cancer cells in laboratory cultures, the stapled peptides reduced the activity of β-catenin by 50%, according to the ACS release.

In a second development, Verdine reported on what he identified to be the first stapled cytokines for treating asthma. Cytokines are hormone-like proteins secreted by the cells of the immune system and other body systems that help orchestrate intercellular signalling. The stapled cytokines moderate the activity of the cytokine, interleukin–13, which asthma patients produce in abnormally large amounts that contribute to asthma attacks, according to the ACS release.

In another development, researchers at the Dana–Farber Cancer Institute, Children's Hospital in Boston, and Harvard University recently reported the use of hydrocarbon double-stapling to remedy the proteolytic instability of a lengthy peptide (5). Specifically, the researchers applied the stapled approach to Fuzeon (enfuvirtide), a 36-amino-acid peptide that inhibits human immunodeficiency virus Type 1 (HIV-1) infection by targeting the viral fusion apparatus.

Fuzeon is marketed by Roche, which developed the drug with the biopharmaceutical company Trimeris. Roche is responsible for the manufacture, sales, marketing, and distribution of Fuzeon. Roche manufactures bulk quantities of Fuzeon drug substance in its Boulder, Colorado, facility and produces finished drug product from bulk drug substance at other Roche facilities, according to Trimeris' 2010 annual filing with the US Securities and Exchange Commission. The finished drug product is shipped to another Roche facility for distribution. The drug had 2010 sales of $88 million.

The researchers noted that enfuvirtide is used as a salvage treatment option because of poor in vivo stability and poor oral bioavailability. To address the proteolytic shortcomings of long peptides as therapeutics, the researchers studied the biophysical, biological, and pharmacological impact of inserting all-hydrocarbon staples into the drug (5). The researchers found that the peptide double-stapling created protease resistance and improved pharmacokinetic properties, including oral absorption. The hydrocarbon staples created a "proteolytic shield" by reinforcing the overall a-helical structure, which slowed the kinetics of proteolysis and also created a complete blockade of peptide cleavage at the constrained sites in the immediate vicinity of the staple (5). The researchers noted the potential of double-stapling to other lengthy peptide-based drugs.

Earlier this year, researchers at the University of Buffalo reported ways of stapling peptide helices. Their approach, dubbed "photoclick stapling," involves the photo-induced 1,3-dipolar cycloaddition reactions (i.e., photoclick chemistry) involving small-ring heterocycles and simple alkenes for both in vitro and live-cell applications. The researchers specifically reported on the photo-induced 1,3-dipolar cycloaddition reaction to staple a peptide dual inhibitor of the p53–Mdm2/Mdmx interactions. The researchers reported that a series of stapled peptide inhibitors were efficiently synthesized and showed dual inhibitory activity in an enzyme-linked immunosorbent assay. The positively charged, stapled peptides showed enhanced cellular uptake along with modest in vivo activity (6). In addition to extending the stapled peptide approached targeting p53–Mdm2/Mdmx interactions, the researchers also are examining BH3–Bcl2/Bcl–xL interactions as potential anticancer therapies.

"There is a lot of potential here." said Qing Lin, assistant professor at the University of Buffalo and lead researcher, in a Feb. 5, 2011, University of Buffalo press release. "Our chemistry is unique. There are not many new drug targets out there today, which partly explains the declining number of FDA-approved new drugs in recent years. So there's a need to come up with new technologies that can overcome this barrier. To this end, stapled peptides could open up a whole host of new targets for therapies."


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