Advancing Peptide Synthesis Through Stapled Peptides - Pharmaceutical Technology

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Advancing Peptide Synthesis Through Stapled Peptides
Stapled peptides offer promise to enable cell permeability, binding to therapeutic targets, and modulation of biological pathways.


Pharmaceutical Technology
Volume 37, Issue 8, pp. 48-50


Advancing Peptide Synthesis Through Stapled Peptides (SHUNYU FAN/GETTY IMAGES)
As a drug type, peptides offer certain benefits, such as specificity and potency, but they also present challenges, such as poor stability and short half-life. Stapled peptides, small modified helical proteins, are an emerging class of peptides that seek to address these limitations. These alpha-helical peptides have structural and functional properties that enable them to penetrate into the cell, bind to the therapeutic target, and modulate biological pathways.


Patricia Van Arnum
Peptides as drugs
Although peptides 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 (1–3). The majority of peptide candidates target extracellular molecules with less than 10% binding to intracellular targets, according to an analysis of the peptide drug pipeline by the Peptide Therapeutics Foundation (1, 4). The most common extracellular targets were G-protein coupled receptors (GPCRs), which include nearly 1000 transmembrane proteins that activate cellular response. During 2000–2008, 60% of peptides entering clinical development targeted GPCRs, and most had agonist activity. Although peptides represent 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 (1, 4). The study found that the average number of new peptide candidates entering clinical development in the 1970s was 1.2 per year, which rose to 4.6 per year in the 1980s, 9.7 per year in the 1990s, and 16.8 per year through 2000–2008 (1, 4).

On a commercial level, there are several peptide drugs that have reached blockbuster status. These include: Teva Pharmaceutical's Copaxone (glatiramer acetate), an L-glutamic acid polymer with L-alanine, L-lysine and L-tyrosine; AbbVie's Lupron (leuprolide acetate), a synthetic nonapeptide analog of the naturally occurring gonadotropin-releasing hormone (GnRH or luteinising hormone-releasing hormone [LHRH]); AstraZeneca's Zoladex (goserelin acetate), a decapeptide and GnRH agonist and synthetic analog of a naturally occurring LHRH; Novartis' Sandostatin (octreotide acetate), a cyclic octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin; and Eli Lilly's Byetta (exenatide), a 39-amino-acid peptide amide (1, 4).

Stapled peptides as a solution
Stapled peptides are a nascent class of peptides that use stabilization technology to enhance potency and cell permeability 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. Peptides and proteins have the size and functionality to effectively modulate intracellular protein–protein interactions, but do not permeate cells and, therefore, re used to modulate extracellular targets (1, 2, 5). 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, 2, 5).


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