TY - JOUR
T1 - Adamantyl derivative as a potent inhibitor of plasmodium FK506 binding protein 35
AU - Harikishore, Amaravadhi
AU - Leow, Min Li
AU - Niang, Makhtar
AU - Rajan, Sreekanth
AU - Pasunooti, Kalyan Kumar
AU - Preiser, Peter Rainer
AU - Liu, Xuewei
AU - Yoon, Ho Sup
PY - 2013/11/14
Y1 - 2013/11/14
N2 - 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.
AB - 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.
KW - chaperone
KW - FK506 binding protein
KW - FKBP35
KW - immunophilin
KW - peptidyl-prolyl-isomerase
UR - http://www.scopus.com/inward/record.url?scp=84887939172&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887939172&partnerID=8YFLogxK
U2 - 10.1021/ml400306r
DO - 10.1021/ml400306r
M3 - Article
AN - SCOPUS:84887939172
SN - 1948-5875
VL - 4
SP - 1097
EP - 1101
JO - ACS Medicinal Chemistry Letters
JF - ACS Medicinal Chemistry Letters
IS - 11
ER -