Adamantyl Derivative As a Potent Inhibitor of <i>Plasmodium</i> FK506 Binding Protein 35

Abstract

FKBP35, FK506 binding protein family member, in <i>Plasmodium</i> species displays a canonical peptidyl-prolyl isomerase (PPIase) activity and is intricately involved in the protein folding process. Inhibition of <i>Pf</i>FKBP35 by FK506 or its analogues were shown to interfere with the in vitro growth of <i>Plasmodium falciparum</i>. In this study, we have synthesized adamantyl derivatives, Supradamal (SRA/4a) and its analogues SRA1/4b and SRA2/4c, which demonstrate submicromolar inhibition of <i>Plasmodium falciparum</i> FK506 binding domain 35 (FKBD35) PPIase activity. SRA and its analogues not only inhibit the in vitro growth of <i>Plasmodium falciparum</i> 3D7 strain but also show stage specific activity by inhibiting the trophozoite stage of the parasite. SRA/4a also inhibits the <i>Plasmodium vivax</i> FKBD35 PPIase activity and our crystal structure of <i>Pv</i>FKBD35 in complex with the SRA provides structural insights in achieving selective inhibition against <i>Plasmodium</i> FKBPs