HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

Abstract
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.
AuthorsMonika Saini, Che Julius Ngwa, Manisha Marothia, Pritee Verma, Shakeel Ahmad, Jyoti Kumari, Sakshi Anand, Vandana Vandana, Bharti Goyal, Soumyananda Chakraborti, Kailash C Pandey, Swati Garg, Soumya Pati, Anand Ranganathan, Gabriele Pradel, Shailja Singh
JournalBiochemical pharmacology (Biochem Pharmacol) Vol. 212 Pg. 115567 (06 2023) ISSN: 1873-2968 [Electronic] England
PMID37088154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2023 Elsevier Inc. All rights reserved.
Chemical References
  • Prohibitins
  • Artemisinins
  • Antimalarials
Topics
  • Humans
  • Animals
  • Plasmodium falciparum (genetics)
  • Parasites
  • Prohibitins
  • Saccharomyces cerevisiae (genetics)
  • Malaria, Falciparum (parasitology)
  • Artemisinins (pharmacology)
  • Antimalarials (pharmacology, therapeutic use)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: