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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Selenomab antibodies are engineered monoclonal antibodies developed at the Scripps Research Institute (US) (Figure 7.29). They include one or more translationally incorporated selenocysteine residues. The nucleophilic reactivity of the selenol group of a selenocysteine residue allows highly efficient site-specific conjugation of payloads. Selenocysteine is particularly reactive, allowing fast, single-step, efficient reactions under near physiological conditions.Diagram showing the production of Selenomab-drug conjugates based on electrophilic reaction of a linker-payload construct with selenocysteine residues.
Enzymatic Amino Acid Deprivation Therapies Targeting Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Carla S. S. Teixeira, Henrique S. Fernandes, Sérgio F. Sousa, Nuno M. F. S. A. Cerqueira
Beyond the depletion effect of MGL, this enzyme can also be administered in combination with the prodrug selenomethionine. The MGL can produce methyl-selenol from the selenomethionine, which causes oxidation of thiol groups generating toxic superoxide molecules that cause cell death. By this way, MGL can be fused with a specific antigen to target the tumour cell and, then, the selenomethionine is administrated, being active only in the area where the MGL is located (Zhao et al., 2006; Guillen et al., 2014).
How can we improve the design of small molecules to target thioredoxin reductase for treating cancer?
Published in Expert Opinion on Drug Discovery, 2021
The unique chemical properties of the selenol group in Sec, in particular, its high nucleophilicity and susceptibility to oxidation, are indispensable for its function in selenoenzymes, including TrxR. In addition, as the Sec residue is exposed on the surface of TrxR, it is the target of the majority of the current TrxR inhibitors, which form either covalent or coordinate bond with the Sec residue. Some inhibitors targeting solely the Sec may generate SECTRAP, leading to a shift of TrxR function [8]. We have extensively reviewed TrxR inhibitors published in literatures and claimed in patents [3,5,7]. Readers are recommended to refer to these references for details. Some TrxR/Trx inhibitors, e.g. ethaselen and PX-12, entered clinical trials for cancer treatment. However, due to the presence of much higher concentration of cysteine (Cys) residue and the thiol group in the Cys having similar chemical reactivity to the selenol group in the Sec [9], how to minimize the interference from the Cys residue is a high challenge in developing Sec-targeting TrxR inhibitors. In this editorial, we will present perspectives regarding the improvement of the design of TrxR inhibitors for treating cancer.
Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Alessio Nocentini, Andrea Angeli, Fabrizio Carta, Jean-Yves Winum, Raivis Zalubovskis, Simone Carradori, Clemente Capasso, William A. Donald, Claudiu T. Supuran
An overview of the main new chemotypes acting as CAIs discovered up until now is shown in Figure 6, in which the “fresh” discovery of the ninhydrins is also mentioned126. Indeed, ninhydrins, such as compound 10, possess a gem-diol stable functionality which has been shown by means of kinetic and computational techniques to coordinate to the metal ion from the enzyme active site126. Furthermore, Figure 7 shows the X-ray crystal structures of some of the new chemotypes detected in the last period, such as the selenol 1195 (Figure 7(A)), unsubstituted ninhydrin 10126 (Figure 7(B)) and a catechol derivative 12127 (Figure 7(C)) which has been recently reported to bind to hCA II by a new inhibition mechanism. Like many phenols, the catechol 12 is anchored to the zinc-coordinated water molecule, but being a diphenol, the second OH moiety additionally binds to the “deep water” molecule in the active site. As mentioned above, selenol 11 and the ninhydrin 10 (Chart 1) directly coordinate to the zinc ion in the enzyme active site (Figure 7). Many of these inhibition mechanisms were thoroughly reviewed in ref.128.
The Effect of Intravenous Selenium on Oxidative Stress in Critically Ill Patients with Acute Respiratory Distress Syndrome
Published in Immunological Investigations, 2019
Ata Mahmoodpoor, Hadi Hamishehkar, Kamran Shadvar, Zohreh Ostadi, Sarvin Sanaie, Seied Hadi Saghaleini, Nader D. Nader
Selenium plays a vital role in synthesis and function of GPx family and catalysis if hydrogen peroxide. GPx molecules are represented in either reduced monomeric glutathione form (GSH) or as the oxidized form of glutathione disulfide (GS–SG) (Metnitz et al., 1999). Type 1 GPx is putatively expressed in all mammalian cells, and it is the most abundant form in the lung parenchyma. The antioxidant mechanism involves oxidation of the selenol of a selenocysteine residue by hydrogen peroxide. This selenenic acid (RSeOH) group is then formed as the main product of this reaction. Through a two-step process, the selenenic acid is then converted back to the GS-SeR and water by the reduced form GPx (Bhabak and Mugesh, 2010). Serum selenium levels are lower in critically ill patients as compared to healthy controls. A recently published study showed that low serum selenium level carries a significant risk and it is associated with a poorer prognosis in patients with respiratory diseases (Lee et al., 2016).