title: Quercetin interferes with iron metabolism in Leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity.
abstract: OBJECTIVE
  The possibility of developing antileishmanial drugs was evaluated by intervention in the parasite's iron metabolism, utilizing quercetin (Qr) under in vivo conditions, and identifying the target of this lipophilic metal chelator against Leishmania donovani.
  
  
  METHODS
  Interaction between Qr and serum albumin (SA) was studied by using the intrinsic fluorescence of Qr as a probe. The effect of treatment with Qr and SA on the proliferation of amastigotes was determined by evaluating splenic parasite load. Disintegration of parasites in response to combination treatment was assessed from ultrastructural analysis using a transmission electron microscope. Quenching of the tyrosyl radical of ribonucleotide reductase (RR) in treated amastigotes was detected by an electron paramagnetic resonance study.
  
  
  RESULTS
  Treatment with a combination of Qr and SA increased bioavailability of the flavonoid and proved to be of major advantage in promoting the effectiveness of Qr towards the repression of splenic parasite load from 75%, P < 0.01 to 95%, P < 0.002. Qr-mediated down-regulation of RR (P < 0.05), catalysing the rate-limiting step of DNA synthesis in the pathogens, could be related to the deprivation of the enzyme of iron which in turn destabilized the critical tyrosyl radical required for its catalysing activity.
  
  
  CONCLUSIONS
  Results have implications for improved leishmanicidal action of Qr in combination with SA targeting RR and suggest future drug design based on interference with the parasite's iron metabolism under in vivo conditions.
authors.affiliation: Indian Association for the Cultivation of Science, Kolkata 700032, India.
authors.forename: Gargi
authors.initials: G
authors.lastname: Sen
authors.forename: Sibabrata
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Manju
authors.initials: M
authors.lastname: Ray
authors.forename: Tuli
authors.initials: T
authors.lastname: Biswas
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology; D006224:Cricetinae; D007501:Iron / Q000378:metabolism*; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism* / Q000648:ultrastructure; D007896:Leishmaniasis / Q000188:drug therapy; D008968:Molecular Conformation; D011794:Quercetin / Q000737:chemistry / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012709:Serum Albumin / Q000378:metabolism; D013154:Spleen / Q000473:pathology
chemical_list: D000981:Antiprotozoal Agents; D012709:Serum Albumin; D011794:Quercetin; D007501:Iron; D012264:Ribonucleotide Reductases