Abstract
BackgroundSchistosomiasis is a disease caused by parasitic worms and more than 200 million people are infected worldwide. The emergence of resistance to the most commonly used drug, praziquantel (PZQ), makes the development of novel drugs an urgent task. 3-oxoacyl-ACP reductase (OAR), a key enzyme involved in the fatty acid synthesis pathway, has been identified as a potential drug target against many pathogenic organisms. However, no research on Schistosoma japonicum OAR (SjOAR) has been reported. The characterization of the SjOAR protein will provide new strategies for screening antischistosomal drugs that target SjOAR.Methodology/Principal FindingsAfter cloning the SjOAR gene, recombinant SjOAR protein was purified and assayed for enzymatic activity. The tertiary structure of SjOAR was obtained by homology modeling and 27 inhibitor candidates were identified from 14,400 compounds through molecular docking based on the structure. All of these compounds were confirmed to be able to bind to the SjOAR protein by BIAcore analysis. Two compounds exhibited strong antischistosomal activity and inhibitory effects on the enzymatic activity of SjOAR. In contrast, these two compounds showed relatively low toxicity towards host cells.Conclusions/SignificanceThe work presented here shows the feasibility of isolation of new antischistosomal compounds using a combination of virtual screening and experimental validation. Based on this strategy, we successfully identified 2 compounds that target SjOAR with strong antischistosomal activity but relatively low cytotoxicity to host cells.
Highlights
Schistosomiasis is a major tropical endemic disease in developing countries
Multiple sequence alignment analysis revealed that Schistosoma japonicum OAR (SjOAR) was 87%, 32% and 25% identical to the homologs from S. mansoni, Plasmodium falciparum and M. tuberculosis, respectively
Fatty acid biosynthesis is essential for the viability of organisms
Summary
Schistosomiasis is a major tropical endemic disease in developing countries. In China, S. japonicum is the major pathogen of this disease [3]. The treatment and control of schistosomiasis depends almost exclusively on praziquantel (PZQ). This drug has been widely used for nearly 40 years because of its high efficiency and low cost [4]. Developing new antischistosomal lead compounds to curb the emergence of drugresistant schistosomes should be given a high priority. Schistosomiasis is a disease caused by parasitic worms and more than 200 million people are infected worldwide. The emergence of resistance to the most commonly used drug, praziquantel (PZQ), makes the development of novel drugs an urgent task.
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