Metal-Based Antimicrobial Protease Inhibitors

Abstract

Limitations associated with the production cost, metabolic instability, side-effects, resistance and poor pharmacokinetics of organic protease inhibitors (PIs), which form an essential component of the front line HAART treatment for HIV, have fuelled efforts into finding novel, transition metal-based alternatives. Some of the attractive features of metalbased therapeutics include synthetic simplicity, solubility control, redox capability, expansion of coordination number and topography matching of the complex to the protein's active site. Building asymmetry into the complex, which may offer better discrimination between host and rogue cell, can readily be achieved through coordination of chiral ligands to the metal centre. Although the scope of this review has been limited to metal-based agents that have been reported to bind/inhibit HIV-1 and parasitic proteases, some desirables, such as high activity, low dosage, minimal toxicity, crossinhibition, unique binding modes and selectivity, have already been delivered. The variability of the d-block metals, coupled with the availability of designer organic ligands, augers well for the future development of clinical metallo-drugs for deployment against protease-associated, fatal diseases.

1,10-Phenanthroline-5,6-Dione–Based Compounds Are Effective in Disturbing Crucial Physiological Events of Phialophora verrucosa

“…Metal-free phendione exerts its antimicrobial effect in several ways, such as disturbing the microorganism's crucial metal metabolism as well as interfering in its metal ion acquisition and its bioavailability for essential reactions (e.g., inhibiting the activity of metalloproteins), affecting the microbial cell homeostasis and culminating in the blockage of primordial biological events (e.g., nutrition, proliferation, differentiation, adhesion, invasion, dissemination and infection) (Santos et al, 2012 ). Protease inhibition is also a prime cellular target of this class of ligand and its associated metal complexes (Kellett et al, 2013 ). In this context, the aim of the present work was to investigate the effect of phendione and its Ag + and Cu 2+ complexes on P. verrucosa proliferation, ultrastructure, metallopeptidase activity, sterol content and morphogenesis.…”

Silver(I) 1,10-Phenanthroline Complexes Are Active against Fonsecaea pedrosoi Viability and Negatively Modulate Its Potential Virulence Attributes

“…The specificity of enzymatic hydrolysis was confirmed with the high blockage of activity (~90%) by pepstatin A (10 μM), a comercial aspartic peptidase inhibitor, as we previously showed in Palmeira et al [ 15 ]. Kellett et al [ 76 ] discussed the ability of some metallic compounds (metallocarborane, polyoxometalate and copper) acting as protease inhibitors, and their potential use as alternative drugs to organic protease inhibitors currently employed against protease-associated diseases. This review showed that metal-based agents have proteolytic enzymes as targets, are able to bind them and inhibit the wild-type HIV aspartic protease as well as parasitic proteases.…”

Metal Ions Introduced to Proteins by Supramolecular Ligands

“…They form a variety of compounds with interesting spectroscopic and magnetic properties whose practical applications are the subject of ongoing research [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]. In the cell, metals are usually found in their complexed form, either as standalone ions or inside specific planar carrier compounds encapsulated by proteins -e.g.…”