Phenotypic screening of nonsteroidal anti-inflammatory drugs identified mefenamic acid as a drug for the treatment of schistosomiasisResearch in context
Eloi M. Lago,
Marcos P. Silva,
Talita G. Queiroz,
Susana F. Mazloum,
Vinícius C. Rodrigues,
Paulo U. Carnaúba,
Pedro L. Pinto,
Jefferson A. Rocha,
Leonardo L.G. Ferreira,
Adriano D. Andricopulo,
Josué de Moraes
Affiliations
Eloi M. Lago
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil
Marcos P. Silva
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil
Talita G. Queiroz
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil
Susana F. Mazloum
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil
Vinícius C. Rodrigues
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil
Paulo U. Carnaúba
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil
Pedro L. Pinto
Center for Research in Parasitology, Adolfo Lutz Institute, São Paulo, SP, Brazil
Jefferson A. Rocha
Research Group of Natural Science and Biotechnology, Federal University of Maranhão, Grajaú, MA, Brazil
Leonardo L.G. Ferreira
Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, Physics Institute of Sao Carlos, University of Sao Paulo, São Carlos, SP, Brazil
Adriano D. Andricopulo
Laboratory of Medicinal and Computational Chemistry, Center for Research and Innovation in Biodiversity and Drug Discovery, Physics Institute of Sao Carlos, University of Sao Paulo, São Carlos, SP, Brazil
Josué de Moraes
Research Center for Neglected Diseases, University of Guarulhos, Praça Tereza Cristina, 229, Centro, 07023-070, Guarulhos, SP, Brazil; Corresponding author.
Background: Treatment and control of schistosomiasis, one of the most insidious and serious parasitic diseases, depend almost entirely on a single drug, praziquantel. Since the funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, 73 nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used in medical and veterinary fields were evaluated for their anti-schistosomal properties. Methods: The efficacy of NSAIDs was first tested against adult Schistosoma mansoni ex vivo using phenotypic screening strategy, effective drugs were further tested in a murine model of schistosomiasis. The disease parameters measured were worm and egg burden, hepato- and splenomegaly. Findings: From 73 NSAIDs, five (mefenamic acid, tolfenamic acid, meclofenamic acid, celecoxib, and diclofenac) were identified to effectively kill schistosomes. These results were further supported by scanning electron microscopy analysis. In addition, the octanol-water partition coefficient, both for neutral and ionized species, revealed to be a critical property for the ex vivo activity profile. Compounds were then tested in vivo using both patent and a prepatent S. mansoni infection in a mouse model. The most effective NSAID was mefenamic acid, which highly reduced worm burden, egg production, and hepato- and splenomegaly. Interpretation: The treatment regimen used in this study is within the range for which mefenamic acid has been used in clinical practice, thus, it is demonstrated the capacity of mefenamic acid to act as a potent anti-schistosomal agent suitable for clinical repurposing in the treatment of schistosomiasis. Keywords: Schistosomiasis, Nonsteroidal anti-inflammatory drugs, Mefenamic acid, Anthelmintic, Schistosomicidal activity
