title: Dimerization of β-tryptase inhibitors, does it work for both basic and neutral P1 groups?
abstract: The tetrameric folding of β-tryptase and the pair-wise distribution of its substrate binding sites offer a unique opportunity for development of inhibitors that span two adjacent binding sites. A series of dimeric inhibitors with two basic P1 moieties was discovered using this design strategy and exhibited tight-binder characteristics. Using the same strategy, an attempt was made to design and synthesize dimeric inhibitors with two neutral-P1 groups in hope to exploit the dimeric binding mode to achieve a starting point for further optimization. The unsuccessful attempt, however, demonstrated the important role played by Ala190 in neutral-P1 binding and casted further doubt on the possibility of developing neutral-P1 inhibitors for β-tryptase.
authors.affiliation: Molecular Innovative Therapeutics, Sanofi Pharmaceuticals, United States. guyan.liang@verizon.net
authors.forename: Guyan
authors.initials: G
authors.lastname: Liang
authors.forename: Yong Mi
authors.initials: YM
authors.lastname: Choi-Sledeski
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Yong
authors.initials: Y
authors.lastname: Gong
authors.forename: Eric W
authors.initials: EW
authors.lastname: MacMillan
authors.forename: Joseph
authors.initials: J
authors.lastname: Tsay
authors.forename: Keith
authors.initials: K
authors.lastname: Sides
authors.forename: Jennifer
authors.initials: J
authors.lastname: Cairns
authors.forename: Berndt
authors.initials: B
authors.lastname: Kulitzscher
authors.forename: David J
authors.initials: DJ
authors.lastname: Aldous
authors.forename: Isabelle
authors.initials: I
authors.lastname: Morize
authors.forename: Henry W
authors.initials: HW
authors.lastname: Pauls
mesh_terms: D001665:Binding Sites; D055503:Protein Multimerization / Q000187:drug effects*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D053802:Tryptases / Q000037:antagonists & inhibitors*
chemical_list: D015842:Serine Proteinase Inhibitors; D053802:Tryptases