Design and evaluation of pharmacological tools for studying the immunomodulatory function of a parasitic protein in CD

Leader: Amaury Farce

Workpackage: WP4

Studies of schistosome-host interactions have revealed that the regulation of host immune activity is involved in schistosome survival. The use of complete schistosome eggs has shown value in the treatment of inflammatory diseases, especially IBD. Previous research conducted at U995 has identified a 28 KDa anti-oxidant, pro-Th2 glutathione S transferase (shP28GST). These results were validated in an animal model of colitis, and enabled the initiation of a Phase II clinical trial in CD (ACROHNEM). Glutathione production is responsible for the antioxidant activity and an increase in the prostaglandin D2 level.

The purpose of this project is to determine which of these activities is responsible for the reduction in intestinal inflammation. In silico analysis of the active site will help us to define the pharmacophoric elements required to bind P28GST. Further refinements will provide information about the enzyme’s two mechanisms of action on the atomic level. On this basis, we will virtually screen compounds able to selectively inhibit one of the activities. They will be tested in vitro for their inhibitory potential in an enzymatic assay for GST activity, and a second assay will attempt to confirm their lack of effect on PGD2 production, and vice versa. The molecules with an interesting activity profile at this stage will subsequently be tested in an in vivo model of TNBS-induced colitis, once the absence of toxicity has been confirmed.

We shall therefore seek to develop pharmacological tools and refine our understanding of the mechanism underlying shP28GST’s anti-inflammatory activity. This in-depth knowledge will be a stepping stone to further improvement of the protein’s efficacy by preferentially directing its activity towards the pathway that results in the greatest efficiency in the treatment of CD.

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