Strategy for the synthesis of multivalent peptide-based nonsymmetric dendrimers by native chemical ligation

A strategy for the synthesis of multivalent peptide-based nonsymmetric dendrimers by native chemical ligation using poly(lysine) dendritic wedges as scaffolds is presented.     

Probing Functional Heteromeric Chemokine Protein–Protein Interactions through Conformation‐Assisted Oxime Ligation

Protein–protein interactions (PPIs) govern most processes in living cells. Current drug development strategies are aimed at disrupting or stabilizing PPIs, which require a thorough understanding of PPI mechanisms. Examples of such PPIs are heteromeric chemokine interactions that are potentially involved in pathological disorders such as cancer, atherosclerosis, and HIV. It remains unclear whether this functional modulation is mediated by heterodimer formation or by the additive effects of mixed chemokines on their respective receptors. To address this issue, we report the synthesis of a covalent RANTES‐PF4 heterodimer (termed OPRAH) by total chemical synthesis and oxime ligation, with an acceleration of the final ligation step driven by PPIs between RANTES and PF4. Compared to mixed separate chemokines, OPRAH exhibited increased biological activity, thus providing evidence that physical formation of the heterodimer indeed mediates enhanced function.     

NMR characterization of a Cu(I)-bound peptide model of copper metallochaperones: insights on the role of methionine

The first NMR structure of a Cu(I)-bound metallochaperone model with the conserved sequence MT/HCXXC revealed that at pH ～3.0 and ～6.8 Cu(I) binds through one Cys and the Met rather than the two Cys residues, differently than at pH ～8.5. This suggests a possible role of Met in metal transport.     

Design and synthesis of a bimodal target-specific contrast agent for angiogenesis

[structure: see text] A bimodal target-specific contrast agent based on a cyclic peptide containing the target-specific NGR sequence, gadolinium(III) diethylenetriaminepentaacetic acid (Gd(III)DTPA), and Oregon Green 488 (OG488) suitable for both MR imaging and optical imaging of angiogenesis is developed. The synthetic strategy for this target-specific contrast agent exploits the use of highly efficient, chemoselective reactions, such as native chemical ligation, and gives a straightforward approach for double labeling of peptides in general.     

A supramolecular approach to multivalent target-specific MRI contrast agents for angiogenesis

The synthesis of a cyclic peptide-Gd(III)DTPA molecule equipped with biotin is presented, yielding a well-defined multivalent MRI contrast agent after its coupling to avidin.     

Noncovalent Synthesis of Protein Dendrimers

The covalent synthesis of complex biomolecular systems such as multivalent protein dendrimers often proceeds with low efficiency, thereby making alternative strategies based on noncovalent chemistry of high interest. Here, the synthesis of protein dendrimers using a strong but noncovalent interaction between a peptide and complementary protein is proposed as an efficient strategy to arrive at dendrimers fully functionalized with protein domains. The association of S‐peptide to S‐protein results in the formation of an active enzyme (ribonuclease S) and therefore serves as an ideal system to explore this synthetic approach. Native chemical ligation was used to couple four S‐peptides by means of their C‐terminal thioester to a cysteine‐functionalized dendritic scaffold, thus yielding a tetravalent S‐peptide wedge. A fully functional ribonuclease S tetramer was prepared by addition of four equivalents of S‐protein. Biophysical techniques (isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), and mass spectrometry) and an enzymatic activity assay were used to verify the formation of the multivalent complex. The noncovalent synthetic strategy presented here provides access to well‐defined, dynamic, semisynthetic protein assemblies in high yield and is therefore of interest to the field of nanomedicine as well as biomaterials.     

Application of an omonasteine ligation strategy for the total chemical synthesis of the BRD7 bromodomain

The use of omonasteine (Omo) in sequential peptide ligation strategies extends the scope of homocysteine (Hcy) ligation to longer, methionine-rich proteins. Hcy-to-Omo conversion can be performed on-resin, while the Omo-to-Hcy deprotection can be performed in situ after peptide ligation. This strategy was successfully applied in the synthesis of the BRD7 bromodomain.