Your browser doesn't support javascript.
loading
Targeting Artemisinin-Resistant Malaria by Repurposing the Anti-Hepatitis C Virus Drug Alisporivir.
Chaurasiya, Ayushi; Kumari, Geeta; Garg, Swati; Shoaib, Rumaisha; Anam, Zille; Joshi, Nishant; Kumari, Jyoti; Singhal, Jhalak; Singh, Niharika; Kaushik, Shikha; Kahlon, Amandeep Kaur; Dubey, Neha; Maurya, Mukesh Kumar; Srivastava, Pallavi; Marothia, Manisha; Joshi, Prerna; Gupta, Kanika; Saini, Savita; Das, Gobardhan; Bhattacharjee, Souvik; Singh, Shailja; Ranganathan, Anand.
Afiliación
  • Chaurasiya A; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Kumari G; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Garg S; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Shoaib R; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Anam Z; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Joshi N; Department of Life Sciences, School of Natural Sciences, Shiv Nadar Universitygrid.410868.3, Greater Noida, Uttar Pradesh, India.
  • Kumari J; Department of Life Sciences, School of Natural Sciences, Shiv Nadar Universitygrid.410868.3, Greater Noida, Uttar Pradesh, India.
  • Singhal J; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Singh N; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Kaushik S; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Kahlon AK; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Dubey N; Department of Molecular Microbiology, Washington University, St. Louis, Missouri, USA.
  • Maurya MK; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Srivastava P; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Marothia M; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Joshi P; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Gupta K; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Saini S; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Das G; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Bhattacharjee S; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Singh S; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
  • Ranganathan A; Special Centre for Molecular Medicine, Jawaharlal Nehru Universitygrid.10706.30, New Delhi, India.
Antimicrob Agents Chemother ; 66(12): e0039222, 2022 12 20.
Article en En | MEDLINE | ID: mdl-36374050
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 ± 0.23) and artemisinin-resistant (PfKelch13R539T with Ri 1.15 ± 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.
Asunto(s)
Palabras clave

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Malaria Falciparum / Artemisininas / Malaria / Antimaláricos Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2022 Tipo del documento: Article País de afiliación: India

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Malaria Falciparum / Artemisininas / Malaria / Antimaláricos Límite: Humans Idioma: En Revista: Antimicrob Agents Chemother Año: 2022 Tipo del documento: Article País de afiliación: India