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

Ayushi Chaurasiya, Geeta Kumari, Swati Garg, Rumaisha Shoaib, Zille Anam, Nishant Joshi, Jyoti Kumari, Jhalak Singhal, Niharika Singh, Shikha Kaushik, Amandeep Kaur Kahlon, Neha Dubey, Mukesh Kumar Maurya, Pallavi Srivastava, Manisha Marothia, Prerna Joshi, Kanika Gupta, Savita Saini, Gobardhan Das, Souvik BhattacharjeeShailja Singh, Anand Ranganathan

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 PfCyclophilin 19B, confirmed through biophysical assays with a Kd value of 354.3 nM. Alisporivir showed potent antimalarial activity against chloroquine-resistant (PfRKL-9 with resistance index [Ri] 2.14 6 0.23) and artemisinin-resistant (PfKelch13R539T with Ri 1.15 6 0.04) parasites. The Ri is defined as the ratio between the IC50 values of the resistant line to that of the sensitive line. To further investigate the mechanism involved, we analyzed the expression level of PfCyclophilin 19B in artemisinin-resistant P. falciparum (PfKelch13R539T). Semiquantitative real-time transcript, Western blot, and immunofluorescence analyses confirmed the overexpression of PfCyclophilin 19B in PfKelch13R539T. A 50% inhibitory concentration in the nanomolar range, together with the targeting of PfCyclophilin 19B, suggests that alisporivir can be used in combination with artemisinin. Since artemisinin resistance slows the clearance of ring-stage parasites, we performed a ring survival assay on artemisinin-resistant strain PfKelch13R539T and found significant decrease in parasite survival with alisporivir. Alisporivir was found to act synergistically with dihydroartemisinin and increase its efficacy. Furthermore, alisporivir exhibited antimalarial activity in vivo. Altogether, with the rational target-based Repurposing of alisporivir against malaria, our results support the hypothesis that targeting resistance mechanisms is a viable approach toward dealing with drug-resistant parasite.

Original languageEnglish (US)
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number12
DOIs
StatePublished - Dec 2022

Keywords

  • PfCyclophilin 19B
  • alisporivir
  • antimalarial
  • artemisinin resistance
  • cyclosporin A

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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