Chemical Synthesis of Bioactive Proteins

Abstract

Nature has developed a plethora of protein machinery to operate and maintain nearly every task of cellular life. These processes are tightly regulated via post-expression modifications-transformations that modulate intracellular protein synthesis, folding, and activation. Methods to prepare homogeneously and precisely modified proteins are essential to probe their function and design new bioactive modalities. Synthetic chemistry has contributed remarkably to protein science by allowing the preparation of novel biomacromolecules that are often challenging or impractical to prepare via common biological means. The ability to chemically build and precisely modify proteins has enabled the production of new molecules with novel physicochemical properties and programmed activity for biomedical research, diagnostic, and therapeutic applications. This minireview summarizes recent developments in chemical protein synthesis to produce bioactive proteins, with emphasis on novel analogs with promising in vitro and in vivo activity.

An Iron‐Catalyzed Protein Desulfurization Method Reminiscent of Aquatic Chemistry

“…Therefore, we sought to exemplify the usefulness of the method by synthesizing polypeptides of biological significance, a typical application where efficient and operationally simple protocols are desirable. [29] The first example shown in Figure 8 describes the synthesis of dermaseptin B2, an antibacterial peptide produced by the frog Phyllomedusa bicolor. [30] Dermaseptin B2 produced through the one-pot NCL/ironcatalyzed desulfurization process proved indistinguishable by LC-MS from an authentic sample produced by solid phase peptide synthesis (SPPS) (see Supplementary Figure S76).…”

Dendronization of chitosan to afford unprecedent thermoresponsiveness and tunable microconfinement

“…42,47 Furthermore, long polymer chains also tend to weaken the inherent biological properties of polysaccharides due to the presence of a large proportion of synthetic polymers in the matrices. 22,25,40,47–50 Therefore, it still remains challenging to develop a convenient methodology for the modification of CS, aiming at improving its properties and functions, and at the same time, retaining or even enriching its bio-related properties. 40,42,51…”

Enabling Peptide Ligation at Aromatic Junction Mimics via Native Chemical Ligation and Palladium-Mediated S-Arylation

“…Chemical protein synthesis provides powerful means to produce synthetic proteins for a variety of applications, ranging from mechanistic investigations to the development of novel bioactive compounds. , This has been achieved by combining a set of synthetic strategies that predominantly capitalize on solid-phase peptide synthesis (SPPS) and chemoselective ligation technology . Such a combination, which is often combined with postsynthetic transformations, enables the production of synthetic proteins in a rigorous manner.…”

“…In this reaction, peptide segments bearing an N-terminal Cys and a C-terminal thioester are reacted in solution through a trans -thioesterification step, followed by an intramolecular S- to N-acyl shift to provide a native amide bond. This approach enables the synthesis of medium-to-large proteins with post-translational modifications (PTMs) as well as noncanonical tags for various applications. − …”