Targeting Artemisinin-Resistant Malaria by Repurposing the Anti-Hepatitis C Virus Drug Alisporivir

Abstract

The emergence of Plasmodium falciparum resistance raises an urgent need to find new antimalarial drugs. Here, we report the rational repurposing of the anti-hepatitis C virus drug, alisporivir, a nonimmunosuppressive analog of cyclosporin A, against artemisinin-resistant strains of P. falciparum . In silico docking studies and molecular dynamic simulation predicted strong interaction of alisporivir with Pf Cyclophilin 19B, confirmed through biophysical assays with a K d value of 354.3 nM.

Prefoldins are novel regulators of the unfolded protein response in artemisinin resistant Plasmodium falciparum malaria

“…Clinical ART resistance is defined as a parasite clearance half-life ≥ 5 h from a patient’s blood post-treatment. To measure ART resistance in vivo , assays that measure the linear decline of parasitemia in patients after drug treatment are used ( 22 ). In vitro studies involve the use of ring-stage survival assay (RSA) that is considered the golden standard for in vitro measurement of artemisinin resistance.…”

“…To evaluate the effect of Biperiden in Pf Kelch13 R539T ART-resistance parasites, a ring survival assay was performed as previously described ( 22 , 40 ). Briefly, Percoll purified early ring stage parasite (0–3-h ring post-invasion) was treated with DHA (700 nM) for 6 h. Post-washing with iRPMI, the parasite was treated with BPD (1 μM), and incubated at 37º C for 66 h. The parasitemia was calculated by counting the number of ∼3000 parasitized cells.…”

Tackling emerging artemisinin resistance by modulating the defensive oxido-reductive mechanism of human malaria parasite by repurposing Nitrofurantoin

“…To evaluate the efficacy of NTF on PfKelch13 R539T parasites, ring stage survival assay (RSA) was performed as described previously [35]. Briefly, percoll-purified schizonts were grown to early ring stage (0-3 h post-invasion), and exposed to different concentrations of NTF (6-120 µM) and DHA (700 nM) alone as well as in combination for 6 h. Following 6 h incubation cultures were washed and incubated again for 66 hr.…”