Study of the effect of palladacycle compounds on Schistosoma mansoni and evaluation of its potential use in the fight against Schistosomiasis

• Grant number: 18/19191-4
• Support Opportunities: Regular Research Grants
• Start date: March 01, 2025
• End date: February 28, 2027
• Field of knowledge: Biological Sciences - Parasitology - Helminthology of Parasites
• Principal Investigator: Katia Cristina Pereira Oliveira Santos
• Grantee: Katia Cristina Pereira Oliveira Santos
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Ana Carolina Tahira ; Clara Lúcia Barbiéri Mestriner ; Daniel Moreno Garcia ; Leyva Cecilia Vieira de Melo ; Murilo Sena Amaral ; Sergio Verjovski Almeida

Abstract

Schistosomiasis is a neglected parasitic disease caused by S. mansoni trematode, affecting 200 million individuals in 76 countries. The parasite has a complex biological cycle, with six distinct stages of development and two hosts, one intermediate (mollusk) and one definitive (man).The treatment of schistosomiasis is carried out by the oral administration of praziquantel, which has low toxicity and is very efficient in eliminating adult worms but not schistosomula. However, some strains of the parasite are resistant to this medication. The mass treatment favors this resistance routinely carried out in regions with high endemicity. In this context, searching for new therapeutic alternatives is relevant and necessary.It has already been demonstrated that the paladacycle complexes, DPPE 1.1 and DPPE 1.2, have leishmanicidal activity, low toxicity and inhibit the activity of cysteine proteinases, specifically cathepsin B from Leishmania spp. Cathepsin B constitutes a factor in the pathogenicity of S. mansoni, as it is responsible for most of the hydrolysis of hemoglobin, the parasite's primary source of amino acids, and it has been demonstrated that inhibition of this enzyme causes a delay in development and limitation of the viability of this helminth. Within this approach, it is believed that paladacycle compounds have potential schistosomicidal activity.In this context, this proposal aims to establish the complete cycle of the parasite on UNIFESP's premises and establish a drug testing platform on schistosomula at different stages of development. Once established, we intend to study the possible effects of paladacycle compounds on the adult worm and schistosomula stages of S. mansoni using in vitro and in vivo experiments and elucidate the possible mechanism of action. The expectation is that exposure of S. mansoni to these complex palladacycles will result in impaired development, parasite viability and drastic changes in oviposition. These results will allow exploring the use of DPPE 1.1 and DPPE 1.2 as a new therapeutic approach to combat schistosomiasis and as an auxiliary tool in elucidating the role of cathepsin B in parasite development. (AU)