Disulfide | EPFL Graph Search

In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In biology, disulfide bridges formed between thiol groups in two cysteine residues are an important component of the secondary and tertiary structure of proteins. Persulfide usually refers to compounds. In inorganic chemistry disulfide usually refers to the corresponding anion S22− (−S−S−). Organic disulfides Symmetrical disulfides are compounds of the formula . Most disulfides encountered in organo sulfur chemistry are symmetrical disulfides. Unsymmetrical disulfides (also called heterodisulfides) are compounds of the formula . They are less common in organic chemistry, but most disulfides in nature are unsymmetrical. Properties The disulfide bonds are strong, with a typical bond dissociation energy of 60 kcal/mo

Mechanical Activation of Chemical Bonds at Polymer Interfaces

Julian Nicolas Bleich

Polymer brushes are a specific class of polymer thin films in which each chain is tethered to the underlying substrate via one chain end. In sufficiently densely grafted assemblies, the individual polymer chains are forced into an extended chain conformation and form a brush-like structure, colloquially referred to as polymer brush. Upon incubation in a good solvent, polymer brushes experience swelling which leads to a tension at the polymer brush - substrate interface. This tension is believed to mechanically facilitate cleaving reactions at the tethering point resulting in the detachment of polymer chains, a process which is known as degrafting. Degrafting, and in the case of crosslinked polymer brushes delamination, has been reported for a large variety of polymer brushes and surface materials. Even though this phenomenon is already known for more than two decades, in depth understanding of the underlying mechanism is lacking and quantitative description of the process is rare. This thesis aims to gain further understanding of the phenomenon by quantitative description of the degrafting process. Further, swelling induced mechanical activation at the tethering point of the polymer to the underlying substrate is discussed in the context of polymer mechanochemistry and presented as a tool to selectively facilitate mechanophore cleavage at the interface. Chapter 1 provides a short historical review on the development of polymer mechanochemistry and gives an overview of commonly applied techniques in the field. The concept of polymer mechanochemistry is then extended to polymer brushes and the discussion results in a number of issues and research questions which are addressed in the subsequent chapters. The preparation and characterization of polymer brushes is not trivial. In Chapter 2 limitations and challenges with focus on experimental reproducibility and thin film characterization are discussed. Chapter 3 discusses the influence of a number of factors, i.e. grafting density and molecular weight of the polymer brush, solvent quality and salt concentration in the incubation medium, on the degrafting process of hydrophilic brushes in aqueous media. Further, the degrafting behavior of polymer brushes prepared from different monomers is compared. It is attempted to correlate degrafting behavior with polymer brush swelling. Contradicting results concerning the actual cleaving point of chains in polymer brushes are found in literature. In Chapter 4 presents structures incorporating only one single potential cleaving point. However, non-specific degrafting could not completely be suppressed. Further, a disulfide bond and oxy-norbornene moiety, commonly used mechanophores, were introduced at the anchoring point. In Chapter 5 the limitation of unwanted background hydrolysis was circumvented by investigating degrafting processes in dry organic media. Specific cleavage of the two mechanophores, disulfide and oxy-norbornene, could be demonstrated.

EPFL2021

Development of Stapling Methods by Selective Side Chain Modifications of Bioactive Peptides

Christopher Matthew Bandeli Kourra

Cyclic peptide therapeutics fill the gap between small molecules (5000 Da) as a separate class of drugs, combining the advantages of both in terms of high selectivity, bioavailability, synthetic accessibility and low toxicity. However, their conformational flexibility and proteolytic instability results in fast metabolism. Therefore, modification of their chemical and structural properties at the proteolytically vulnerable sites can circumvent these deficiencies. Several strategies exist to stabilise peptides through local or global constraints, side chain functionalisation or amide bond surrogates. This thesis describes the development and application of two chemical transformations to peptides with the aim of greatly enhancing their metabolic stability either via side chain to side chain cyclisation or disulfide modification. Following the functionalisation, a comparative evaluation of the pharmacological properties of the modified peptides was conducted with respect to the parent peptides. The first cyclisation strategy aimed to apply the redox-neutral chemistry developed in the burgeoning field of borrowing hydrogen technology to peptides, as a new class of tolerable substrates. These would contain the requisite amine and alcohol functional groups enabling their direct coupling to form the lactam or N-alkylated cycle. Numerous investigations into this transformation with a plethora of substrates and catalysts did not lead to the desired cyclisation. For the second approach, a simple one-pot procedure for the 'stapling' of disulfide bonds in native peptides was developed. Tris(2-carboxyethyl)phosphine mediated reduction of the disulfide bond was followed by concomitant insertion of a 'doubly electrophilic' carbon bridge to form a physiologically stable dithioacetal bond. The reaction was performed under mild, biocompatible reaction conditions, allowing for the facile conversion of native peptides into more stable analogues. The protocol was applicable to a range of bioactive peptides with a multitude of reactive functional groups demonstrating the high versatility of this approach. The importance and utility of the modified analogues were verified by testing their binding affinity and biological activity against the corresponding parent peptides. The impact of the disulfide modification on these properties for each peptide were analysed on a case-by-case basis. The SCS modified analogues of Oxytocin and Vasopressin maintained binding affinities in the same order of magnitude as their respective parent compounds across all corresponding receptors. Nevertheless, this was not the case for SCS-Octreotide and SCS-Somatostatin. Those peptides which maintained comparable binding affinities were then tested for their functional activity at the receptors of biological interest. SCS-Oxytocin retained its agonist potency displaying sub-nanomolar activity at the Oxytocin receptor, whilst SCS-Vasopressin exhibited sub micromolar functional response at the Vasopressin 1A receptor. Then the stability of the modified peptides in human serum was evaluated. In some cases, the enhancement in serum stability was vastly increased. In particular our modified SCS-Oxytocin analogue clearly demonstrated a significant improvement in serum half-life, as well as heat and pH stability over its native parent form. This disulfide stapling method could have wide-reaching application for the development of more stable therapeutic analogues.

EPFL2016

Partial characterization of natural and recombinant human soluble CD23

Gerardo Turcatti

The purification to homogeneity of an active soluble 25 kDa fragment of CD23, produced in insect cells using the baculovirus expression system, is described. Peptide mapping and analysis by Edman degradation and mass spectrometry permitted partial characterization of the protein. A total of 165 out of 172 residues, including N-terminal and C-terminal regions, were mapped. The positions of the two disulphide bonds in the IgE-binding region were also determined: residue 110 is joined to residue 124, and residue 42 to residue 133. Natural CD23 25 kDa fragment was also analysed and found to possess the same disulphide bond arrangement. These results extend the previously noted sequence similarity with lectins to elements of secondary structure.

1992