Copper salisylaldoxime (CuSAL) imparts protective efficacy against visceral leishmaniasis by targeting Leishmania donovani topoisomerase IB.
In vitro and in vivo anti-leishmanial efficacy of copper salisylaldoxime (CuSAL), a transition metal complex, was evaluated and the underlying mechanism was studied. In vitro studies revealed that 30 μM of CuSAL causes 96% reduction in parasite burden in infected macrophages. CuSAL is least toxic in host cells. A dose of 5 mg/kg bodyweight per mice on alternate days (5 doses) gives ∼97% protection in both liver and spleen. Moreover, CuSAL potentially inhibits the catalytic activity of LdTOPILS and causes apoptosis of Leishmania parasites through induction of intracellular ROS generation and activation of caspase-like proteases. Interestingly, CuSAL does not inhibit the catalytic activity of human topoisomerase I. The present study illuminated that CuSAL, has potent anti-leishmanial activity, which selectively targets LdTOPILS; and is a safe for human. Therefore, this compound might be highly promising candidate to develop the rational approaches for chemotherapy of human leishmaniasis.
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700032, India.
Manoj Kumar
MK
Singh
Dept of Pediatrics, Emory University, Atlanta, GA 30322, USA.
Siddhartha Kumar
SK
Bhaumik
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700032, India.
Subir
S
Karmakar
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700032, India.
Joydeep
J
Paul
Dept of Chemistry, Seth Anandram Jaipuria College, Calcutta University, Kolkata, 700005, India.
Sudeshna
S
Sawoo
Infectious Diseases and Immunology Division, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Kolkata, 700032, India.
Hemanta K
HK
Majumder
Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Hajipur, Vaishali, 844102, India. Electronic address: amitavik@gmail.com.
Amit
A
Roy
D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000494:pharmacology* / Q000627:therapeutic use; D053938:DNA Fragmentation; D007893:Leishmania donovani / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D007898:Leishmaniasis, Visceral / Q000188:drug therapy*; D008099:Liver / Q000469:parasitology / Q000503:physiopathology; D008111:Liver Function Tests; D008264:Macrophages / Q000187:drug effects / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000032:analysis; D013154:Spleen / Q000469:parasitology; D059004:Topoisomerase I Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D000981:Antiprotozoal Agents; D056831:Coordination Complexes; D010091:Oximes; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; C000616265:copper salicylaldoxime; D053148:Caspase 3
Copper salisylaldoxime (CuSAL); DNA topoisomerase I and apoptosis; Leishmania donovani