40958-31-4Relevant academic research and scientific papers
Programming Bioactive Architectures with Cyclic Peptide Amphiphiles
Kuan, Seah Ling,Wang, Tao,Raabe, Marco,Liu, Weina,Lamla, Markus,Weil, Tanja
, p. 1347 - 1353 (2015)
We present a versatile approach for the synthesis of cyclic peptide amphiphiles of the hormone somatostatin (SST) with tunable lipophilic tails to program bioactive nanoarchitectures. A novel bis-alkylation reagent is synthesized that facilitates the functionalization of SST with a thiol anchor. Different hydrophobic moieties are introduced inspired by a biomimetic palmitoylation approach which opens access to cyclic peptide amphiphiles that display rich self-organization and cell membrane interactions. Made to order: Cyclic peptide amphiphiles prepared by a bioinspired approach are employed to program various bioactive nanoarchitectures that display rich self-organization and cell membrane interactions.
Bromopyridazinedione-mediated protein and peptide bioconjugation
Chudasama, Vijay,Smith, Mark E. B.,Schumacher, Felix F.,Papaioannou, Danai,Waksman, Gabriel,Baker, James R.,Caddick, Stephen
, p. 8781 - 8783 (2011)
Bromopyridazinedione-mediated bioconjugation to a cysteine containing protein and a disulfide containing peptide is described. The conjugates are cleavable in an excess of thiol, including cytoplasmically-relevant concentrations of glutathione, and show a high level of hydrolytic stability. The constructs have the potential for four points of chemical attachment.
Robust synthesis of C-terminal cysteine-containing peptide acids through a peptide hydrazide-based strategy
Zuo, Chao,Yan, Bing-Jia,Zhu, Han-Ying,Shi, Wei-Wei,Xi, Tong-Kuai,Shi, Jing,Fang, Ge-Min
supporting information, p. 5698 - 5702 (2019/06/18)
A new robust strategy was reported for the epimerization-free synthesis of C-terminal Cys-containing peptide acids through mercaptoethanol-mediated hydrolysis of peptide thioesters prepared in situ from peptide hydrazides. This simple-to-operate and highly efficient method avoids the use of derivatization reagents for resin modification, thus providing a practical avenue for the preparation of C-terminal Cys-containing peptide acids.
“Doubly Orthogonal” Labeling of Peptides and Proteins
Tessier, Romain,Ceballos, Javier,Guidotti, Nora,Simonet-Davin, Raphael,Fierz, Beat,Waser, Jerome
supporting information, p. 2243 - 2263 (2019/08/08)
Herein, we report a cysteine bioconjugation methodology for the introduction of hypervalent iodine compounds onto biomolecules. Ethynylbenziodoxolones (EBXs) engage thiols in small organic molecules and cysteine-containing peptides and proteins in a fast and selective addition onto the alkynyl triple bond, resulting in stable vinylbenziodoxolone hypervalent iodine conjugates. The conjugation occurs at room temperature in an open flask under physiological conditions. The use of an azide-bearing EBX reagent enables a “doubly orthogonal” functionalization of the bioconjugate via strain-release-driven cycloaddition and Suzuki-Miyaura cross-coupling of the vinyl hypervalent iodine bond. We successfully applied the methodology on relevant and complex biomolecules, such as histone proteins. Through single-molecule experiments, we illustrated the potential of this doubly reactive bioconjugate by introducing a triplet-state quencher close to a fluorophore, which extended its lifetime by suppressing photobleaching. This work is therefore expected to find broad applications for peptide and protein functionalization. Understanding the molecular basis of life is essential in the search for new medicines. Chemical biology develops molecular tools for studying biological processes, setting the basis for new diagnostics and therapeutics, and relies heavily on the ability to selectively modify biomolecules. Two approaches have been especially fruitful: (1) selective modification of natural biomolecules and (2) selective reaction between non-natural functionalities in the presence of biomolecules (the so-called orthogonal bioconjugation). In our work, we contribute to both by transferring highly reactive hypervalent iodine reagents to cysteine residues in proteins and peptides. The obtained bioconjugates retain the reactive hypervalent bonds, which can be selectively functionalized via a metal-mediated reaction. Combined with a traditional azide tag, our approach allows a doubly orthogonal functionalization of biomolecules and is hence expected to be highly useful in chemical biology. Chemical biology develops molecular tools for studying biological processes, setting the basis for new diagnostics and therapeutics, and relies heavily on the ability to modify selectively biomolecules. In our work, we introduce hypervalent iodine bonds into peptides and proteins, via functionalization of cysteine, by using unique cyclic reagents developed in our group. The hypervalent bond can then be selectively modified in the presence of both natural and synthetic functional groups, opening new opportunities for applications in chemical biology.
Aryloxymaleimides for cysteine modification, disulfide bridging and the dual functionalization of disulfide bonds
Marculescu, Cristina,Kossen, Hanno,Morgan, Rachel E.,Mayer, Patrick,Fletcher, Sally A.,Tolner, Berend,Chester, Kerry A.,Jones, Lyn H.,Baker, James R.
supporting information, p. 7139 - 7142 (2014/07/07)
Tuning the properties of maleimide reagents holds significant promise in expanding the toolbox of available methods for bioconjugation. Herein we describe aryloxymaleimides which represent 'next generation maleimides' of attenuated reactivity, and demonstrate their ability to enable new methods for protein modification at disulfide bonds.
Bis-sulfide bioconjugates for glutathione triggered tumor responsive drug release
Wang, Tao,Ng, David Y. W.,Wu, Yuzhou,Thomas, Jessica,Tamtran, Thuy,Weil, Tanja
supporting information, p. 1116 - 1118 (2014/01/17)
The reaction of bis-sulfone conjugation reagents with disulfide bonds allows the site-specific modification of various peptides and proteins. Herein, we present the intracellular disintegration of bis-sulfide containing somatostatin bioconjugates under co
Bioactive unnatural somatostatin analogues through bioorthogonal iodo-and ethynyl-disulfide intercalators
Pfisterer, Anne,Eisele, Klaus,Chen, Xi,Wagner, Manfred,Muellen, Klaus,Weil, Tanja
experimental part, p. 9697 - 9707 (2011/10/08)
Iodo-and ethynyl-containing bisalkylating bioconjugation agents 5 and 8 were achieved and allow the introduction of reactive unnatural substituents into proteins and peptides whilst the bioactive 3D structure is retained. Derivatives of the peptide hormon
Protein modification, bioconjugation, and disulfide bridging using bromomaleimides
Smith, Mark E. B.,Schumacher, Felix F.,Ryan, Chris P.,Tedaldi, Lauren M.,Papaioannou, Danai,Waksman, Gabriel,Caddick, Stephen,Baker, James R.
experimental part, p. 1960 - 1965 (2010/05/12)
The maleimide motif is widely used for the selective chemical modification of cysteine residues in proteins. Despite widespread utilization, there are some potential limitations, including the irreversible nature of the reaction and, hence, the modification and the number of attachment positions. We conceived of a new class of maleimide which would address some of these limitations and provide new opportunities for protein modification. We report herein the use of mono- and dibromomaleimides for reversible cysteine modification and illustrate this on the SH2 domain of the Grb2 adaptor protein (L111C). After initial modification of a protein with a bromo- or dibromomaleimide, it is possible to add an equivalent of a second thiol to give further bioconjugation, demonstrating that bromomaleimides offer opportunities for up to three points of attachment. The resultant protein-maleimide products can be cleaved to regenerate the unmodified protein by addition of a phosphine or a large excess of a thiol. Furthermore, dibromomaleimide can insert into a disulfide bond, forming a maleimide bridge, and this is illustrated on the peptide hormone somatostatin. Fluorescein-labeled dibromomaleimide is synthesized and inserted into the disulfide to construct a fluorescent somatostatin analogue. These results highlight the significant potential for this new class of reagents in protein modification.
Kinetics and equilibria of the thiol/disulfide exchange reactions of somatostatin with glutathione
Rabenstein, Dallas L.,Weaver, Kim H.
, p. 7391 - 7397 (2007/10/03)
Rate and equilibrium constants are reported for the thiol/disulfide exchange reactions of the peptide hormone somatostatin with glutathione (GSH). GSH reacts with the disulfide bond of somatostatin to form somatostatin-glutathione mixed disulfides (Cys3-SH, Cys14-SSG and Cys3-SSG, Cys14-SH), each of which can react with another molecule of GSH to give the reduced dithiol form of somatostatin and GSSG. The mixed disulfides also can undergo intramolecular thiol/disulfide exchange reactions to re-form the disulfide bond of somatostatin or to interconvert to the other mixed disulfide. Analysis of the forward and reverse rate constants indicates that, at physiological concentrations of GSH, the intramolecular thiol/disulfide exchange reactions that re-form the disulfide bond of somatostatin are much faster than reaction of the mixed disulfides with another molecule of GSH, even though the intramolecular reaction involves closure of a 38-membered ring. Thus, even though the disulfide bond of somatostatin is readily cleaved by thiol/disulfide exchange, it is rapidly reformed by intramolecular thiol/disulfide exchange reactions of the somatostatin-glutathione mixed disulfides. By comparison with rate constants reported for analogous reactions of model peptides measured under random coil conditions, it is concluded that disulfide bond formation by intramolecular thiol/disulfide exchange in the somatostatin-glutathione mixed disulfides is not completely random, but rather it is directed to some extent by conformational properties of the mixed disulfides that place the thiol and mixed disulfide groups in close proximity. A reduction potential of -0.221 V was calculated for the disulfide bond of somatostatin from the thiol/disulfide exchange equilibrium constant.
