Deng, Xiaoyan, Myrand-Lapierre, Marie-Eve, Matthews, Kerryn, Santoso, Aline Teresa, Du, Yiling, Ryan, Katherine S and Ma, Hongshen (2015) REDUCED DEFORMABILITY OF PARASITIZED RED BLOOD CELLS AS A BIOMARKER FOR ANTIMALARIAL DRUG EFFICACY. Malaria Journal.

Abstract

Background
Malaria remains a challenging and fatal infectious disease throughout the developing
world. Malaria progressively induces structural and functional changes causing
rigidification (loss of deformability) of infected red blood cells. Antimalarials may
accelerate this process, thereby allowing the infected erythrocyte to be removed from the
circulation earlier. The rapid spread of antimalarial drug resistance increases the urgency
for the development of new drugs. Many biomarkers, including malaria specific genes
and parasite synthesized proteins and metabolites, have been developed to evaluate drug
efficacy as well as to screen new drugs.
Methods
Recently, we developed a microfluidic mechanism, called the multiplexed fluidic plunger
that provides sensitive and rapid measurement of single red blood cell deformability.
Here, we systematically evaluated the deformability changes of late stage trophozoite
infected-RBCs after treatment with various well known as well as unknown antimalarials.
Results
We show a concentration and time - dependent response relationship that exists between
chloroquine treatment and iRBCs deformability change. We determined that
rigidification of trophozoite-infected RBCs is a universal property of almost all clinical
antimalarial drug treatments. Spiroindolone compounds (+)-SJ733 and NITD246,
inhibitors to a Plasmodium falciparum cation-transporting ATPase ATP4, induced the
highest rigidified trophozoite-infected RBCs. Collectively, these results suggest that
changes in the deformability of iRBCs could be used as a biomarker for antimalarial drug
treatments. Therefore, as a proof-of-principle, we tested a group of bisindole alkaloids.
The results revealed that cladoniamide A, which has a rare scaffold and lower IC50 value
than that of chloroquine may be a promising antimalarial drug candidate.
Conclusions
Our results demonstrate that rigidification of infected-RBCs may be used as a biomarker
for antimalarial drug efficacy as well as for new drug screening. As a proof of principle,
we successfully discovered a potential antimalarial drug.

Item Type:	Article
Date Deposited:	27 Apr 2016 23:45
Last Modified:	27 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/26109