BACKGROUND: Multidrug-resistant Plasmodium is of major concern today. Effective 
vaccines or successful applications of RNAi-based strategies for the treatment 
of malaria are currently unavailable. An unexplored area in the field of malaria 
research is the development of DNA-targeting drugs that can specifically 
interact with parasitic DNA and introduce deleterious changes, leading to loss 
of vital genome function and parasite death.
PRESENTATION OF THE HYPOTHESIS: Advances in the development of zinc finger 
nuclease (ZFN) with engineered DNA recognition domains allow us to design and 
develop nuclease of high target sequence specificity with a mega recognition 
site that typically occurs only once in the genome. Moreover, cell-penetrating 
peptides (CPP) can cross the cell plasma membrane and deliver conjugated 
protein, nucleic acid, or any other cargo to the cytoplasm, nucleus, or 
mitochondria. This article proposes that a drug from the combination of the CPP 
and ZFN systems can effectively enter the intracellular parasite, introduce 
deleterious changes in its genome, and eliminate the parasite from the infected 
cells.
TESTING THE HYPOTHESIS: Availability of a DNA-binding motif for more than 45 
triplets and its modular nature, with freedom to change number of fingers in a 
ZFN, makes development of customized ZFN against diverse target DNA sequence of 
any gene feasible. Since the Plasmodium genome is highly AT rich, there is 
considerable sequence site diversity even for the structurally and functionally 
conserved enzymes between Plasmodium and humans. CPP can be used to deliver ZFN 
to the intracellular nucleus of the parasite. Signal-peptide-based heterologous 
protein translocation to Plasmodium-infected RBCs (iRBCs) and different 
Plasmodium organelles have been achieved. With successful fusion of CPP with 
mitochondrial- and nuclear-targeting peptides, fusion of CPP with 1 more 
Plasmodium cell membrane translocation peptide seems achievable.
IMPLICATIONS OF THE HYPOTHESIS: Targeting of the Plasmodium genome using ZFN has 
great potential for the development of anti-malarial drugs. It allows the 
development of a single drug against all malarial infections, including 
multidrug-resistant strains. Availability of multiple ZFN target sites in a 
single gene will provide alternative drug target sites to combat the development 
of resistance in the future.