TY - JOUR
T1 - Targeting Artemisinin-Resistant Malaria by Repurposing the Anti-Hepatitis C Virus Drug Alisporivir
AU - Chaurasiya, Ayushi
AU - Kumari, Geeta
AU - Garg, Swati
AU - Shoaib, Rumaisha
AU - Anam, Zille
AU - Joshi, Nishant
AU - Kumari, Jyoti
AU - Singhal, Jhalak
AU - Singh, Niharika
AU - Kaushik, Shikha
AU - Kahlon, Amandeep Kaur
AU - Dubey, Neha
AU - Maurya, Mukesh Kumar
AU - Srivastava, Pallavi
AU - Marothia, Manisha
AU - Joshi, Prerna
AU - Gupta, Kanika
AU - Saini, Savita
AU - Das, Gobardhan
AU - Bhattacharjee, Souvik
AU - Singh, Shailja
AU - Ranganathan, Anand
N1 - Publisher Copyright:
Copyright © 2022 American Society for Microbiology. All Rights Reserved.
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - PfCyclophilin 19B
KW - alisporivir
KW - antimalarial
KW - artemisinin resistance
KW - cyclosporin A
UR - http://www.scopus.com/inward/record.url?scp=85144406663&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85144406663&partnerID=8YFLogxK
U2 - 10.1128/aac.00392-22
DO - 10.1128/aac.00392-22
M3 - Article
C2 - 36374050
AN - SCOPUS:85144406663
SN - 0066-4804
VL - 66
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 12
ER -