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The Modification of Cysteine
Published in Roger L. Lundblad, Chemical Reagents for Protein Modification, 2020
Cysteine is far more reactive as the thiolate anion. The pKa for the formation of the thiolate anion is 10.5 with free cysteine but is considerably reduced with the cysteinyl residue in peptide bond. For example, the pKa for the formation of the thiolate anion N-acetylcysteine ethyl ester is 8.5 while with N-formyl cysteine, it is 9.5. It is useful to compare these values with pKa values for other functional groups as is done in Table 1.
Gold Nanoparticles as Promising Agents for Cancer Therapy
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
Nadine Karaki, Hassan Hajj Ali, Assem El Kak
Different stabilizing agents such as ligands, polymers, surfactants, and biomolecules must be used to prevent the uncontrollable growth and aggregation of NPs [65]. Thiolate is the most frequently used stabilizer or capping ligand because it forms more compact nanoparticles by strong gold-thiol bonds (chemisorption) knowing that there are other less used ligand motifs such as amines or phosphines, among others [66].
The Glutathione Redox State and Zinc Mobilization from Metallothionein and Other Proteins with Zinc–Sulfur Coordination Sites
Published in Christopher A. Shaw, Glutathione in the Nervous System, 2018
The control of biological function by thiolate groups of cysteines in proteins is well established. A more recent development is the realization that the reactivity of cysteine thiolate is modulated through zinc coordination and that the special reactivity of the zinc–sulfur bond is also employed for biological control. An early example of this reactivity is the carboxymethylation of horse liver alcohol dehydrogenase with either iodoacetamide or iodoacetate, which specifically modifies just one of the two zinc–sulfur (cysteine) bonds of the catalytic zinc atom without loss of zinc. This specificity is achieved through an arginine side chain, which orients and directs the reagent toward the active site (Li and Vallee 1963; Zeppezauer, Jörnvall, and Ohlsson 1975).
Discovery of novel drugs for Chagas disease: is carbonic anhydrase a target for antiprotozoal drugs?
Published in Expert Opinion on Drug Discovery, 2022
Alane Beatriz Vermelho, Giseli Capaci Rodrigues, Alessio Nocentini, Felipe R. P. Mansoldo, Claudiu T. Supuran
Thiols possess a similar mechanism of action to sulfonamides, as they bind to the zinc ion in the enzyme’s active site (as thiolate anions) and substitute the non-protein zinc ligand [54,83]. Derivatives of 5-mercapto-1,3,4-thiadiazoles were investigated as TcCA inhibitors by Pan et al. [29]. The mercapto moiety in its anionic form acted as an efficient zinc-binding group. The thiols were more potent TcCA inhibitors (KI values of 21.1 − 79.0 nM) than many sulfonamides investigated in the same work [29]. The thiols are also more lipophilic than sulfonamides, thus better penetrating the parasite membrane. In the mentioned study [29], all the investigated thiols inhibited the growth of two strains of T. cruzi at 256 μM concentrations in vivo, proving that this class of CAIs has a real potential for designing effective TcCA inhibitors. However, the only compounds investigated are the 5-mercapto-1,3,4-thiadiazoles mentioned above.
Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
Published in Xenobiotica, 2020
Kenta Mizoi, Masato Takahashi, Sachiko Sakai, Takuo Ogihara, Masami Haba, Masakiyo Hosokawa
Thioester prodrugs are specifically metabolically activated by HLM because of the high HLM/HIM ratio (Table 2). However, in the comparison of thioesters with the corresponding esters, the hydrolytic activity by hCESs was complicated (Figure 2). The rate at which thioesters are hydrolyzed by HLM and HIM is considered to be higher than the corresponding esters because thiolate anion is more stable than alkoxide ion. However, it is thought that the hydrolysis rate of hCESs became complicated when considering the sulfur atom has lower electronegativity and a larger atomic radius than an oxygen atom, or the steric structure of the substituent. Therefore, these results suggested that the hydrolytic activity of hCESs may be regulated by the balance between steric hindrance and the electron density in a thioester.
Toward the identification of ZDHHC enzymes required for palmitoylation of viral protein as potential drug targets
Published in Expert Opinion on Drug Discovery, 2020
Mohamed Rasheed Gadalla, Michael Veit
The first spatial structures of two ZDHHC proteins might be instrumental to develop specific inhibitors of protein palmitoylation since the process can now be guided by computer-aided drug discovery methods [188]. A new and promising approach are covalent inhibitors of cysteine residues, which might have increased potency over non-covalent analogues and can target enzymes with shallow or highly charged pockets. The thiolate form of cysteine is capable of forming covalent bonds with a wide range of reactive moieties (‘warheads’), which are attached to a lead compound that determines the specificity of binding. Cysteines are rare in proteins, but are essential for the catalytic activity of ZDHHCs [189]. However, it is unclear whether such an approach leads to drugs specific for certain ZDHHCs or whether the binding sites in ZDHHCs for their viral substrates needs to be targeted. In any case, a detailed understanding of the enzymatic reaction mechanism and of the interaction surfaces of ZDHHCs with their substrates is required to successfully develop inhibitors.