title: Potent, low-molecular-weight non-peptide inhibitors of malarial aspartyl protease plasmepsin II.
abstract: A number of single-digit nanomolar, low-molecular-weight plasmepsin II aspartyl protease inhibitors have been identified using combinatorial chemistry and structure-based design. By identifying multiple, small-molecule inhibitors using the parallel synthesis of several focused libraries, it was possible to select for compounds with desirable characteristics including enzyme specificity and minimal binding to serum proteins. The best inhibitors identified have Ki's of 2-10 nM, molecular weights between 594 and 650 Da, between 3- and 15-fold selectivity toward plasmepsin II over cathepsin D, the most closely related human protease, good calculated log P values (2.86-4.56), and no apparent binding to human serum albumin at 1 mg/mL in an in vitro assay. These compounds represent the most potent non-peptide plasmepsin II inhibitors reported to date.
authors.affiliation: Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, USA.
authors.forename: T S
authors.initials: TS
authors.lastname: Haque
authors.forename: A G
authors.initials: AG
authors.lastname: Skillman
authors.forename: C E
authors.initials: CE
authors.lastname: Lee
authors.forename: H
authors.initials: H
authors.lastname: Habashita
authors.forename: I Y
authors.initials: IY
authors.lastname: Gluzman
authors.forename: T J
authors.initials: TJ
authors.lastname: Ewing
authors.forename: D E
authors.initials: DE
authors.lastname: Goldberg
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: J A
authors.initials: JA
authors.lastname: Ellman
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D015800:Protozoan Proteins; D012709:Serum Albumin / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D012709:Serum Albumin; D016282:Aspartic Acid Endopeptidases; C100637:plasmepsin II; D002402:Cathepsin D