Search

Disulfide‐rich peptides and proteins are among the most fascinating bioactive molecules. The difficulties associated with the preparation of these targets have prompted the development of various chemical strategies. Nevertheless, the production of these targets remains very challenging or elusive. Recently, we introduced a strategy for one‐pot disulfide bond formation, tackling most of the previous limitations. However, the effect of the order of oxidation remained an underexplored issue. Herein we report on the complete synthetic flexibility of the approach with respect to the order of oxidation of three disulfide bonds in targets that lack the knot motif. In contrast, our study reveals an essential order of disulfide bond formation in the EETI‐II knotted miniprotein. This synthetic strategy was applied for the synthesis of novel analogues of the plectasin antimicrobial peptide with enhanced activities against methicillin‐resistant Staphylococcus aureus (MRSA), a notorious human pathogen. [ABSTRACT FROM AUTHOR]

Peptides and proteins can be either synthesized using solid-phase peptide synthesis (SPPS) or by applying a combination of SPPS and ligation approaches to address fundamental questions related to human health and disease, among others. The demand for their production either by chemical or biological methods continues to raise significant interests from the synthetic community. In this context, transition metals such as Pd, Ag, Hg, Tl, Au, Zn, Ni, and Cu have also contributed to the field of peptide and protein synthesis such as in peptide conjugation, extending native chemical ligation (NCL), and for regioselective disulfide bonds formation. In this review, we highlight, summarize, and evaluate the use of various transition metals in the chemical synthesis of peptides and proteins with emphasis on recent developments in this exciting research area. [ABSTRACT FROM AUTHOR]

Despite six decades of efforts to synthesize peptides and proteins bearing multiple disulfide bonds, this synthetic challenge remains an unsolved problem in most targets (e.g., knotted mini proteins). Here we show a de novo general synthetic strategy for the ultrafast, high-yielding formation of two and three disulfide bonds in peptides and proteins. We develop an approach based on the combination of a small molecule, ultraviolet-light, and palladium for chemo- and regio-selective activation of cysteine, which enables the one-pot formation of multiple disulfide bonds in various peptides and proteins. We prepare bioactive targets of high therapeutic potential, including conotoxin, RANTES, EETI-II, and plectasin peptides and the linaclotide drug. We anticipate that this strategy will be a game-changer in preparing millions of inaccessible targets for drug discovery. Synthesis of peptides and proteins containing multiple disulfide bonds is challenging, limiting the elucidation of their biological functions. Here, the authors report a general synthetic strategy for fast formation of two and three disulfide bonds in peptides and proteins, and apply it to prepare several therapeutically important peptides. [ABSTRACT FROM AUTHOR]

Reversible attachment of solubilizing tags to hydrophobic peptides to facilitate their purification and ligation is an essential yet challenging task in chemical protein synthesis. The efficient palladium-assisted removal of the solubilizing tag linked to the Cys side chain is reported. The strategy was applied for the efficient preparation of histone protein H4 from two fragments via one-pot operation of ligation, removal of the solubilizing tag, and desulfurization. [ABSTRACT FROM AUTHOR]