Adamantyl Derivative As a Potent Inhibitor of Plasmodium FK506 Binding Protein 35

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 Plasmod...

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Published inACS medicinal chemistry letters Vol. 4; no. 11; pp. 1097 - 1101
Main Authors Harikishore, Amaravadhi, Leow, Min Li, Niang, Makhtar, Rajan, Sreekanth, Pasunooti, Kalyan Kumar, Preiser, Peter Rainer, Liu, Xuewei, Yoon, Ho Sup
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 14.11.2013
Amer Chemical Soc
Subjects
Chemistry, Medicinal
Letter
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
FK506 binding protein
immunophilin
peptidyl-prolyl-isomerase
chaperone
FKBP35
DOMAIN
FALCIPARUM
ASCOMYCIN
FK506-BINDING PROTEIN
CIS-TRANS ISOMERASE
CALCINEURIN
MALARIA PARASITE
TARGETS
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Summary: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.
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ISSN:1948-5875
1948-5875
DOI:10.1021/ml400306r