Identification of Inhibitors of the Schistosoma mansoni VKR2 Kinase Domain

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2(KD)) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivo S. mansoni. Our crystal structure of the SmVKR2(KD) displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.

Automated summary

Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Treatment options are limited, but the study identifies SmVKR2 as a potential drug target. Screening of inhibitors against SmVKR2 led to the identification of compounds that could inhibit its enzymatic activity and induce phenotypic changes in the parasite.