Patchwork Protein Chemistry: A Practitioner's Treatise on the Advances in Synthetic Peptide Stitchery

Abstract

With the study of peptides and proteins at the heart of many scientific endeavors, the omics era heralded a multitude of opportunities for chemists and biologists alike. Across the interface with life sciences, peptide chemistry plays an indispensable role, and progress made over the past decades now allows proteins to be treated as molecular patchworks stitched together through synthetic tailoring. The continuous elaboration of sophisticated strategies notwithstanding, Merrifield's solid-phase methodology remains a cornerstone of chemical protein design. Although the non-practitioner might misjudge peptide synthesis as trivial, routine, or dull given its long history, we comment here on its many advances, obstacles, and prospects from a practitioner's point of view. While sharing our perspectives through thematic highlights across the literature, this treatise provides an interpretive overview as a guide to novices, and a recap for specialists.

Realizing serine/threonine ligation: scope and limitations and mechanistic implication thereof

“…The realization of NCL lies in the super nucleophilicity of the N-terminal cysteine to mediate a chemoselective peptide ligation, thereby enabling merger of two side chain unprotected peptide segments with the generation of the natural Xaa-Cys at the ligation site. Over the past two decades, many advances in the development of strategies and methods to improve and expand the NCL at other amino acids sites (Hackenberger and Schwarzer, 2008; Hemantha et al, 2012; Monbaliu and Katritzky, 2012; Verzele and Madder, 2013). Of particular importance, the success of NCL-desulfurization to realize the peptide ligation at the alanine site (Yan and Dawson, 2001; Wan and Danishefsky, 2007) has initiated the development of NCL at other amine acid sites using synthetic cysteine/selenocysteine surrogates (Canne et al, 1996; Wong et al, 2013c).…”

Untapped Opportunities of Resin‐to‐Resin Transfer Reactions (RRTR) for the Convergent Assembly of Multivalent Peptide Conjugates

“…The field of bioorganic chemistry and chemical biology has recently witnessed a boom in peptide ligation and conjugation strategies, along with the rise of the bioorthogonality concept . Developments include tandem, one‐pot and solid‐phase schemes, and methodologies are pushed up to the limits of synthetic viability.…”

“…The fieldo fb ioorganic chemistry and chemicalb iology has recently witnessed ab oom in peptidel igation and conjugation strategies, [1] along with the rise of the bioorthogonality concept. [2] Developments include tandem,o ne-pot and solidphase schemes, [3,4] and methodologies are pushed up to the limits of synthetic viability.T he use of precisely addressable transacylation systems, [5][6][7] applied in fine-tuned combinations for the sequential, convergento ri terative assembly of polypeptidem olecules, [8][9][10] demonstrates the attained level of sophistication.…”

Benchmarking B-Cell Epitope Prediction with Quantitative Dose-Response Data on Antipeptide Antibodies: Towards Novel Pharmaceutical Product Development

“…As regards their manufacture, they are amenable to production via biotechnological as well as synthetic chemical means, with the latter becoming more practically feasible for increasingly longer polypeptide chains [5]. In terms of biotransformation, they are typically metabolized in vivo via main-chain peptide-bond hydrolysis [6], which is less problematic than the metabolism of more exotic xenobiotics that yields toxic metabolites [7].…”