Small molecule Plasmodium FKBP35 inhibitor as a potential antimalaria agent

Citations Over TimeTop 10% of 2013 papers

Abstract

Malaria parasite strains have emerged to tolerate the therapeutic effects of the prophylactics and drugs presently available. This resistance now poses a serious challenge to researchers in the bid to overcome malaria parasitic infection. Recent studies have shown that FK520 and its analogs inhibit malaria parasites growth by binding to FK506 binding proteins (FKBPs) of the parasites. Structure based drug screening efforts based on three-dimensional structural information of FKBPs from Plasmodium falciparum led us to identify new chemical entities that bind to the parasite FKBP35 and inhibit its growth. Our experimental results verify that this novel compound (D44) modulate the PPIase activity of Plasmodium FKBP35 and demonstrate the stage-specific growth inhibition of Plasmodium falciparum strains. Here, we present the X-ray crystallographic structures of FK506 binding domains (FKBDs) of PfFKBP35 and PvFKBP35 in complex with the newly identified inhibitor providing molecular insights into its mode of action.

Related Papers

• → Comparative Analysis of Calcineurin Inhibition by Complexes of Immunosuppressive Drugs with Human FK506 Binding Proteins(2006)60 cited
• → The Precise Chemical–Physical Nature of the Pharmacore in FK506 Binding Protein Inhibition: ElteX, a New Class of Nanomolar FKBP12 Ligands(2013)37 cited
• → FKBP12 is the only FK506 binding protein mediating T-cell inhibition by the immunosuppressant FK5061(2002)48 cited
• → Molecular cloning of a membrane-associated human FK506- and rapamycin-binding protein, FKBP-13.(1991)173 cited
• → Mutation of FKBP associated protein 48 (FAP48) at proline 219 disrupts the interaction with FKBP12 and FKBP52(2001)9 cited