title: Type I methionine aminopeptidase from Saccharomyces cerevisiae is a potential target for antifungal drug screening.
abstract: OBJECTIVE
  To screen antifungal drug candidates using in vitro and in vivo assays based on type I methionine aminopeptidase from Saccharomyces cerevisiae (ScMetAP1).
  
  
  METHODS
  A colorimetric assay suitable for high throughput screening (HTS) using recombinant ScMetAP1 protein expressed in Escherichia coli was established for antifungal lead discovery. A series of pyridine-2-carboxylic acid derivatives were characterized and a chemical library of 12,800 pure organic compounds was screened with the in vitro ScMetAP1 assay. Active compounds from the in vitro assay were further evaluated by a growth inhibition assay on yeast strain with deletion of ScMetAP1 gene map1 in comparison with the wild-type yeast strain and the yeast strain with deletion of type II enzyme (ScMetAP2) gene map2.
  
  
  RESULTS
  Active ScMetAP1 inhibitors were identified from HTS. Some of the pyridine-2-carboxylic acid derivatives (compound 2 and 3) had selective inhibition of the growth of map2 deletion yeast and weak inhibition on wild-type yeast growth, while no inhibition on map1 deletion yeast.
  
  
  CONCLUSIONS
  ScMetAP1 is a novel potential target for developing antifungal drugs. The in vitro and in vivo ScMetAP1 assays can serve as tools in discovering antifungal drug candidates.
authors.affiliation: National Center for Drug Screening, Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China.
authors.forename: Ling-ling
authors.initials: LL
authors.lastname: Chen
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Jing-ya
authors.initials: JY
authors.lastname: Li
authors.forename: Qun-li
authors.initials: QL
authors.lastname: Luo
authors.forename: Wei-feng
authors.initials: WF
authors.lastname: Mao
authors.forename: Qiang
authors.initials: Q
authors.lastname: Shen
authors.forename: Fa-jun
authors.initials: FJ
authors.lastname: Nan
authors.forename: Qi-zhuang
authors.initials: QZ
authors.lastname: Ye
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D000935:Antifungal Agents / Q000302:isolation & purification* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification; D004926:Escherichia coli / Q000201:enzymology / Q000235:genetics; D063208:Methionyl Aminopeptidases; D011994:Recombinant Proteins / Q000096:biosynthesis; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D000626:Aminopeptidases; D063208:Methionyl Aminopeptidases