title: Adamantyl derivative as a potent inhibitor of Plasmodium FK506 binding protein 35.
abstract: FKBP35, FK506 binding protein family member, in Plasmodium species displays a canonical peptidyl-prolyl isomerase (PPIase) activity and is intricately involved in the protein folding process. Inhibition of PfFKBP35 by FK506 or its analogues were shown to interfere with the in vitro growth of Plasmodium falciparum. In this study, we have synthesized adamantyl derivatives, Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c, which demonstrate submicromolar inhibition of Plasmodium falciparum FK506 binding domain 35 (FKBD35) PPIase activity. SRA and its analogues not only inhibit the in vitro growth of Plasmodium falciparum 3D7 strain but also show stage specific activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the Plasmodium vivax FKBD35 PPIase activity and our crystal structure of PvFKBD35 in complex with the SRA provides structural insights in achieving selective inhibition against Plasmodium FKBPs.
authors.affiliation: School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637665 Singapore.
authors.forename: Amaravadhi
authors.initials: A
authors.lastname: Harikishore
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, 637731 Singapore.
authors.forename: Min Li
authors.initials: ML
authors.lastname: Leow
authors.affiliation: School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637665 Singapore.
authors.forename: Makhtar
authors.initials: M
authors.lastname: Niang
authors.affiliation: School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637665 Singapore.
authors.forename: Sreekanth
authors.initials: S
authors.lastname: Rajan
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, 637731 Singapore.
authors.forename: Kalyan Kumar
authors.initials: KK
authors.lastname: Pasunooti
authors.affiliation: School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637665 Singapore.
authors.forename: Peter Rainer
authors.initials: PR
authors.lastname: Preiser
authors.affiliation: School of Physical and Mathematical Sciences, Nanyang Technological University , 21 Nanyang Link, 637731 Singapore.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Liu
authors.affiliation: School of Biological Sciences, Nanyang Technological University , 60 Nanyang Drive, 637665 Singapore.
authors.forename: Ho Sup
authors.initials: HS
authors.lastname: Yoon
keywords: FK506 binding protein; FKBP35; chaperone; immunophilin; peptidyl-prolyl-isomerase