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2.
J Biol Inorg Chem ; 25(8): 1117-1128, 2020 12.
Article in English | MEDLINE | ID: mdl-33104887

ABSTRACT

Invasive fungal infections (IFIs) are life threatening and existing antifungal drugs are not completely effective due to undesirable side effects and resistance emergence. Azoles are often the treatment of choice for IFIs and growing evidence suggests that copper can act synergistically with these drugs. In this work, we designed a compound bringing together azole and copper(II)-binding groups and studied the molecular mechanisms underlying its biological toxicity. Our results show that both the compound, 4, and its copper(II) complex, Cu.4, are active against Candida spp. We found that Cu.4 acts as a copper(II) ionophore, which results in the intracellular accumulation of reactive oxygen species (ROS), whereas compound 4 is an iron chelator and exerts its toxicity by decreasing iron bioavailability. Interestingly, while 4 is not very toxic to macrophages or HeLa cells, Cu.4 significantly affects their viability. Overall, this work provides evidence of how copper can be combined with azoles to deregulate copper homeostasis, opening new horizons for the development of bifunctional antifungals.


Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Candida/drug effects , Copper/chemistry , Ionophores/chemistry , Triazoles/chemistry , Triazoles/pharmacology , Antifungal Agents/toxicity , Cell Survival/drug effects , HeLa Cells , Humans , Triazoles/toxicity
3.
Methods Enzymol ; 580: 333-64, 2016.
Article in English | MEDLINE | ID: mdl-27586340

ABSTRACT

Peptides are multidentate chiral ligands capable of coordinating different metal ions. Nowadays, they can be obtained with high yield and purity, thanks to the advances on peptide/protein chemistry as well as in equipment (peptide synthesizers). Based on the identity and length of their amino acid sequences, peptides can present different degrees of flexibility and folding. Although short peptide sequences (<20 amino acids) usually lack structure in solution, different levels of structural preorganization can be induced by introducing conformational constraints, such as ß-turn/loop template sequences and backbone cyclization. For all these reasons, and the fact that one is not restricted to use proteinogenic amino acids, small peptidic scaffolds constitute a simple and versatile platform for the development of inorganic systems with tailor-made properties and functions. Here we outline a general approach to the design of short preorganized peptide sequences (10-16 amino acids) for metal ion coordination. Based on our experience, we present a general scheme for the design, synthesis, and characterization of these peptidic scaffolds and provide protocols for the study of their metal ion coordination properties.


Subject(s)
Amino Acids/chemistry , Copper/chemistry , Peptides/chemistry , Protein Engineering/methods , Amino Acid Sequence/genetics , Amino Acids/genetics , Ions/chemistry , Ligands , Peptides/genetics
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