Total chemical synthesis of proteins is usually achieved by assembling unprotected peptide segments using site-specific and chemoselective native peptide ligation methods. Access to large proteins often requires the assembly of at least three segments due to the current limits of solid phase synthesis of individual peptide segments. The aim of this tutorial review is to present the basic concepts and challenges underlying the design of sequential peptide ligation strategies using solution or solid phase chemistry. A special emphasis is given to C-to-N and N-to-C three-segment assembly strategies, which potentially give access to proteins composed of up to 150 amino acid residues.
Jiangsu Provincial Key Lab for the Chemistry and Utilization of Agro-Forest Biomass, Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, Jiangsu Key Lab of Biomass-Based Green Fuels and Chemicals, International Innovation Center for Forest Chemicals and Materials, College of Chemical Engineering, Nanjing Forestry University, Nanjing, Jiangsu 210037, China.
We herein report the efficient synthesis of peptide-benzazepine conjugates from Lys-based peptides and acroleins via Rh(III)-catalyzed double C-H activation. This reaction features mild reaction conditions, broad scope, high atom and step economies, and excellent chemo- and site selectivity. The synthetic utility of this strategy is further demonstrated by scale-up experiments and product derivatizations, including diverse late-stage ligations based on the aldehyde moiety.
Mirror-image proteins, composed of D-amino acids, are an attractive therapeutic modality, as they exhibit high metabolic stability and lack immunogenicity. Development of mirror-image binding proteins is achieved through chemical synthesis of D-target proteins, phage display library selection of L-binders and chemical synthesis of (mirror-image) D-binders that consequently bind the physiological L-targets. Monobodies are well-established synthetic (L-)binding proteins and their small size (~90 residues) and lack of endogenous cysteine residues make them particularly accessible to chemical synthesis.
A regioselective cobalt-catalyzed three-component silylamidation that rapidly and reliably incorporates dioxazolones and silylzinc pivalates into unconjugated alkenyl amides is disclosed. Notably, the unique power of this protocol is demonstrated by the possibility of achieving peptide ligation using peptide-containing dioxazolones or alkenyl amides as the coupling partners. Moreover, this approach is distinguished by its mild condition, synthetic simplicity, and ample scope, thus providing a new platform for modular access to silicon-containing amino acid derivatives and peptides.
Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.
Transpeptidases are specialized enzymes that have evolved for site-selective modification of peptides and proteins at their backbone termini. Approaches for adapting transpeptidases to catalyze side chain modifications are substantially more restricted, and typically rely on large recognition tags or require specific reaction conditions that are not easily compatible with broader applications. Here we show that the engineered asparaginyl ligase AEP1 catalyzes direct isopeptide ligation by accepting an internal 2,3-diaminopropionic acid (Dap) residue adjacent to Leu, a motif that mimics the canonical N-terminal Gly-Leu substrate.
Background: The inflammatory response is associated with cardiac repair and ventricular remodeling after myocardial infarction (MI). The key inflammation regulatory factor thymic stromal lymphopoietin (TSLP) plays a critical role in various diseases. However, its role in cardiac repair after MI remains uncertain.
