Home Blog of Signal Transduction DNA Damage/DNA Repair eIF Characterization of Plasmodium falciparum prohibitins as novel targets to block infection in humans by impairing the growth and transmission of the parasite

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Characterization of Plasmodium falciparum prohibitins as novel targets to block infection in humans by impairing the growth and transmission of the parasite

Prohibitins (PHBs) are highly conserved pleiotropic proteins as they have been shown to mediate key cellular functions. Here, we characterize PHBs encoding putative genes ofPlasmodium falciparum by exploiting different orthologous models. We demonstrated that PfPHB1 (PF3D7_0829200) and PfPHB2 (PF3D7_1014700) are expressed in asexual and sexual blood stages of the parasite. Immunostaining indicated hese proteins as mitochondrial residents as they were found to be localized as branched structures. We further validated PfPHBs as organellar proteins residing in Plasmodium mitochondria, where they interact with each other. Functional characterization was done in Saccharomyces cerevisiae orthologous model by expressing PfPHB1 and PfPHB2 in cells harboring respective mutants. The PfPHBs functionally complemented the yeast PHB1 and PHB2 mutants, where the proteins were found to be involved in stabilizing the mitochondrial DNA, retaining mitochondrial integrity and rescuing yeast cell growth. Further, Rocaglamide (Roc-A), a known inhibitor of PHBs and anti-cancerous agent, was tested against PfPHBs and as an antimalarial. Roc-A treatment retarded the growth of PHB1, PHB2, and ethidium bromide petite yeast mutants. Moreover, Roc-A inhibited growth of yeast PHBs mutants that were functionally complemented with PfPHBs, validating P. falciparum PHBs as one of the molecular targets for Roc-A. Roc-A treatment led to growth inhibition of artemisinin-sensitive (3D7), artemisinin-resistant (R539T) and chloroquine-resistant (RKL-9) parasites in nanomolar ranges. The compound was able to retard gametocyte and oocyst growth with significant morphological aberrations. Based on our findings, we propose the presence of functional mitochondrial PfPHB1 and PfPHB2 in P. falciparum and their druggability to block parasite growth.

 

Comments:

The above passage describes a study characterizing the Plasmodium falciparum prohibitins (PHBs), which are proteins that are involved in key cellular functions. The study shows that PfPHB1 and PfPHB2 are expressed in both asexual and sexual blood stages of the parasite and are localized in the mitochondria. Using a yeast model, the study shows that these proteins are involved in stabilizing mitochondrial DNA and maintaining mitochondrial integrity. The study also shows that Rocaglamide (Roc-A), an inhibitor of PHBs and an anti-cancerous agent, can inhibit the growth of PHB1, PHB2, and ethidium bromide petite yeast mutants, as well as the growth of P. falciparum parasites in nanomolar ranges. The study suggests that PfPHB1 and PfPHB2 could be druggable targets for blocking parasite growth and that Roc-A could be a potential anti-malarial drug.

Related Products

Cat.No. Product Name Information
S7428 Rocaglamide Rocaglamide (Roc-A), isolated from Aglaia species, is a potent inhibitor of heat shock factor 1 (HSF1) activation with IC50 of ~50 nM for HSF1. Rocaglamide inhibits the function of the translation initiation factor eIF4A. Rocaglamide also inhibits NF-κB activity. Rocaglamide exhibits anti-tumor activity.

Related Targets

HSP (HSP90) eIF NF-κB