title: 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.
authors.affiliation: School of Chemical Sciences and the National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. andrew.kellett@dcu.ie
authors.forename: A
authors.initials: A
authors.lastname: Kellett
authors.forename: A
authors.initials: A
authors.lastname: Prisecaru
authors.forename: C
authors.initials: C
authors.lastname: Slator
authors.forename: Z
authors.initials: Z
authors.lastname: Molphy
authors.forename: M
authors.initials: M
authors.lastname: McCann
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000737:chemistry* / Q000494:pharmacology; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D057056:Cysteine Proteases / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008670:Metals / Q000737:chemistry*; D010961:Plasmodium / Q000187:drug effects / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology; D017973:Tungsten Compounds / Q000737:chemistry; D000099294:Polyoxometalates
chemical_list: D000890:Anti-Infective Agents; D056831:Coordination Complexes; D057056:Cysteine Proteases; D017320:HIV Protease Inhibitors; D008670:Metals; D015800:Protozoan Proteins; D017973:Tungsten Compounds; C102296:polyoxometalate I; D000099294:Polyoxometalates