Editorial: Chemical Design and Biomedical Applications of Disulfide-rich Peptides: Challenges and Opportunities

Abstract

Editorial on the Research Topic Chemical Design and Biomedical Applications of Disulfide-rich Peptides: Challenges and Opportunities The last two decades have witnessed of a revolution within the peptide field. From being considered just biochemical tools to becoming a real alternative to both small molecules and biologics as drugs. Currently, there are more than 90 peptides in the market ranging from small di-or tripeptides to large peptides containing more than 30 and even 40 amino acids (Henninot et al., 2018; Al Shaer et al., 2020). Among the last arrivals into the market, ixazomib (Ninlar R), which is an N-acylated, C-boronic acid dipeptide approved by the Food and Drug Administration (FDA) in 2015 for the treatment of multiple myeloma, and macimorelin (Macrilen R), a small pseudopeptide formed by three residues, approved by FDA in 2016 for the treatment of adult growth hormone deficiency, are examples of the first group (Al Shaer et al., 2020). Adlyxin (lixisenatide R), a 44 amino acid peptide, authorized by the same agency in 2016 for the treatment of the diabetes, could exemplify the second group (Al Shaer et al., 2020). Fifty years ago, it was entirely predictable that small peptides entered into the market. The dipeptide enapril, for example, which is still one of the most prescribed medications around the world, was marketed in 1984. The reason is that they were synthesized as if they were small molecules. The possibility of having a sufficient amount and, more importantly, the required purity for human administration was unthinkable for medium-sized peptides. In those days, the future of this kind of peptides was more as biochemical tools than as drugs. What was the impetus that changed this paradigm? Without a doubt, this is the development of the solid phase peptide synthesis (SPPS) technology by Merrifield (1963), and most importantly, its subsequent refinement. SPPS is a clear example of how transformative research can be done from basic research. In 1963, Merrifield published a new and a very efficient method for the synthesis of a simple tetrapeptide (Leu-Ala-Gly-Val) (Merrifield, 1963). At first, the method was not well-received by the entire Academy, it was even criticized. Thus, a reviewer of the first article characterizes SPPS as a "travesty,. .. not chemistry at all, a concept which should be suppressed by the community" (Marshall, 2008). However, the boom of peptide-based drugs is due to the implementation of SPPS in both research and production modes. The use of SPPS in research allows the synthesis of small amounts of peptides in a very short period of time and with sufficient purity

Cysteine protecting groups: applications in peptide and protein science

“…5,6 Disulfide-containing peptides have also gained huge interest as therapeutic agents. [7][8][9] In 1953 Vigneaud, Ressler, Swan, Roberts, Katsoyannis, and Gordon, demonstrated the chemical synthesis of the hormone oxytocin, a disulfide containing peptide that is the focus of a great deal of therapeutic research (Fig. 1a).…”

Solid-Phase Synthesis of C-Terminus Cysteine Peptide Acids

“…Somatostatin Elongation Using Selected Bases for Fmoc Removal. First, linear somatostatin (H-AGCKNFFWKTFTSC-OH) and linear D- 14 Cys-somatostatin (H-AGCKNFFWKTFTSc-OH) were synthesized. The separation of the peptides in HPLC was then studied using artificial mixtures of the D and L epimers in proportion (1:9, 1:19, and 1:99).…”

“…The solid-phase approach [solid-phase peptide synthesis (SPPS)], using a fluorenylmethoxycarbonyl (Fmoc)/ tert -butyl ( t Bu) protection scheme, , is the method of choice for the preparation of peptides in both research and production modes. Although cystine/Cys-containing peptides are not an exception, their synthesis brings about more challenges than that of homodetic peptides where only the peptide bond is present. ,, The disulfide bond is formed mostly when the elongation of the peptide chain has taken place. Although this formation can occur while the peptide is still anchored to the resin, the most efficient way to achieve this bond is when the unprotected peptide has been cleaved from the resin .…”

“…Although cystine/Cys-containing peptides are not an exception, their synthesis brings about more challenges than that of homodetic peptides where only the peptide bond is present. 3,13,14 The disulfide bond is formed mostly when the elongation of the peptide chain has taken place. Although this formation can occur while the peptide is still anchored to the resin, the most efficient way to achieve this bond is when the unprotected peptide has been cleaved from the resin.…”

“…Figure 4. HPLC of mixtures of linear D-14 Cys-somatostatin and linear somatostatin in proportion (1:9, 1:19, and 1:99). In the inset table, the result of the integration is presented.…”