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Peptides Gain Traction in Drug Development
Peptides as drugs
Although a small portion of total drug candidates, the number of peptide drugs entering clinical development has increased during the past several decades, according to the Peptide Therapeutics Foundation analysis, which excluded insulins (3). The study found that the average number of new peptide candidates entering clinical development in the 1970s was 1.2 per year and rose to 4.6 per year in the 1980s, 9.7 per year in the 1990s, and 16.8 per year through 2000–2008 (3). During 2000–2008, peptides entering clinical study were most frequently treatments for cancer and metabolic disorders (including diabetes and obesity), respectively, representing 18% and 17% of peptide drug development. Decreases were observed for peptides studied as therapies for treating allergies, immunological disorders and cardiovascular diseases (3).
On a commercial level, several peptide-based therapeutics have reached blockbuster status, defined as having sales of $1 billion
or more, or near blockbuster status (3). These drugs, using 2011 global sales figures from company annual financial reports,
Approaches to peptide synthesis
Stapled peptides use peptide-stabilization technology to enhance potency and cell permeability of a drug to address pharmacological limitations of small molecules and existing biologics in intracellular protein–protein interactions. Although small molecules are able to penetrate cells, the large binding surfaces for intracellular protein–protein interactions often make small-molecule modulators ineffective. Although peptides and proteins have the size and functionality to effectively modulate intracellular protein–protein interactions, they often do not permeate cells and therefore are used to modulate extracellular targets, such as receptors (1, 10). Stapled peptides seek to resolve those problems. Because many undruggable therapeutic targets include those protein–protein interactions in which alpha-helices are required in lock-and-key-type mechanisms, an approach is to design alpha-helical peptides that have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target, and modulate the biological pathway (1, 10). Aileron stabilizes peptides by "stapling" them with hydrocarbon bonds into an alpha-helix. Once constrained in the alpha-helix structure, the peptides are protected from degradation by proteases. The stabilized alpha-helical peptides can penetrate cells by energy-dependent active transport and typically have a higher affinity to large protein surfaces (1, 2, 10).
Researchers at the New York Structural Biology Center recently reported on high-resolution solution nuclear magnetic resonance techniques with dynamic light-scattering to characterize a family of hydrocarbon-stapled peptides with known inhibitory activity against HIV-1 capsid assembly to evaluate the various factors that modulate activity. The researchers reported that helical peptides share a common binding motif but differ in charge, the length, and position of the staple. The research showed that the peptides share a propensity to self-associate into organized polymeric structures mediated predominantly by hydrophobic interactions between the olefinic chain and the aromatic side-chains from the peptide. The researchers also detailed the structural significance of the length and position of the staple and of olefinic bond isomerization in stabilizing the helical conformation of the peptides as potential factors influencing polymerization (11).
Cyclic peptides . In April 2012, researchers at Carnegie Mellon University reported on their manufacturing method for a synthetic form of a cyclic peptide. Macrocyclic peptides with multiple disulfide cross-linkages, such as those produced by plants and those found in nonhuman primates, hold potential as drugs because of their broad biological activities and high chemical, thermal, and enzymatic stability (12). Because of their intricate spatial arrangement and elaborate interstrand cross-linkages, some macrocyclic peptides are difficult to prepare in large quantities and high purity because of the nonselective nature of disulfide-bond formation (12).
In the current study, the Carnegie Mellon researchers focused on RTD-1, a cyclic peptide held together by three disulfide bonds. RTD-1 has a broad range of antibacterial, antifungal and antiviral capabilities and has been shown to inhibit HIV from entering cells. The researchers created a mimic of RTD-1. While the outside of the mimic peptide maintained the same amino acids as the original, the researchers replaced the disulfide bonds at its center with noncovalent Watson–Crick hydrogen bonds without significantly affecting the biological activity of the peptide. The researchers say the work provides a general strategy for engineering conformationally rigid, cyclic peptides without the need for disulfide-bond reinforcement (12).
They tested the efficacy of the mimic RTD-1 by mixing the peptide with Escheria coli, Listeria, Staphylococcus, and Salmonella—bacteria that RTD-1 typically protects against.
The mimic proved to be effective in killing each of the types of bacteria tested by the researchers, which included both gram-positive and gram-negative bacterial strains. Furthermore, the mimic peptide worked by binding to the bacteria's cell membrane, not its DNA or RNA, decreasing the probability that the bacteria could develop resistance to the peptide, according to an Apr. 13, 2012, Carnegie Mellon University press release. The researchers plan to see if the mimic RTD-1 is effective against other types of pathogens, including antibiotic-resistant bacteria. They also plan to apply their method to manufacture mimics of other cyclic peptides, according to the university release.
Other approaches. In 2011, the biopharmaceutical company Sutro Biopharma formed a multiyear collaboration with Pfizer for the research, development, and commercialization of novel peptide-based therapeutics. The partnership gives Pfizer access to peptides that have been difficult to produce using conventional technologies using a biochemical protein synthesis technology platform developed by Sutro, In 2008, Pfizer acquired CovX, a biopharmaceutical company with a technology platform that links therapeutic peptides to an antibody scaffold. The peptide targets the disease while the antibody scaffold allows the peptide to remain in the body long enough to achieve therapeutic benefit. The technology thereby allows for better half-life extension and bioavailability to support optimal dosing regimens for peptide therapeutics.
Patricia Van Arnum is executive editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, firstname.lastname@example.org
1. T. Sawyer, Chem. Biol. Drug. Des. 73 (1), 3–6 (2009).
2. W. Wolfson, Chem. & Biol. 16 (9), 910–911 (2009).
3. Peptide Therapeutics Foundation, Development Trends for Peptide Therapeutics Report (San Diego, 2010).
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10. P. Van Arnum, Pharm. Technol. 35 (5), 56–60 (2011).
11. S. Bhattacharya et al., Biopolymers 97 (5), 253–264 (2012).
12. Ly et al., J. Am. Chem. Soc. 134 (9), 4041–4044 (2012).