3-Oxoacyl-ACP Reductase from Schistosoma japonicum: Integrated In Silico-In Vitro Strategy for Discovering Antischistosomal Lead Compounds

Liu, Jian; Dyer, Dave; Wang, Jipeng; Wang, Shuqi; Du, Xiaofeng; Xu, Bin; Zhang, Haobing; Wang, Xiaoning; Hu, Wei

doi:10.1371/journal.pone.0064984

Cited by 16 publications

(11 citation statements)

References 40 publications

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“…A combination of molecular docking and in vitro analysis led to the discovery of another triclosan analogue (OAR27), able to inhibit Schistosoma japonicum FabG with an IC 50 value of 51 μM. The compound (OAR27) displayed cytotoxicity in human liver carcinoma cells [ 6 ], indicating OAR27 may possess some activity against the KR domain of human FAS, yet this could possibly be reduced with optimisation using the structures of Yp FabG and other bacterial FabG enzymes as a basis for such drug design.…”

Section: Resultsmentioning

confidence: 99%

Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis

Nanson

Forwood

2015

PLoS ONE

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Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

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Section: Resultsmentioning

confidence: 99%

Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis

Nanson

Forwood

2015

PLoS ONE

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“…In addition to glycolytic enzymes (PYK and GAPDH), also these taking part in fatty enzyme metabolism are considered important drug targets. Similarly to 3-oxoacyl-ACP reductase, an important candidate in antischistosomal combat ( 48 ). As the above mentioned enzymatic proteins have not been identified as immunogenic in the adult E. granulosus ( 9 ), our study reports their possible antigenicity in an adult tapeworms for the first time.…”

Section: Discussionmentioning

confidence: 99%

Immunoproteomics and Surfaceomics of the Adult Tapeworm Hymenolepis diminuta

et al. 2018

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In cestodiasis, mechanical and molecular contact between the parasite and the host activates the immune response of the host and may result in inflammatory processes, leading to ulceration and intestinal dysfunctions. The aim of the present study was to identify antigenic proteins of the adult cestode Hymenolepis diminuta by subjecting the total protein extracts from adult tapeworms to 2DE immunoblotting (two-dimensional electrophoresis combined with immunoblotting) using sera collected from experimentally infected rats. A total of 36 protein spots cross-reacting with the rat sera were identified using LC-MS/MS. As a result, 68 proteins, including certain structural muscle proteins (actin, myosin, and paramyosin) and moonlighters (heat shock proteins, kinases, phosphatases, and glycolytic enzymes) were identified; most of these were predicted to possess binding and/or catalytic activity required in various metabolic and cellular processes, and reported here as potential antigens of the adult cestode for the first time. As several of these antigens can also be found at the cell surface, the surface-associated proteins were extracted and subjected to in-solution digestion for LC-MS/MS identification (surfaceomics). As a result, a total of 76 proteins were identified, from which 31 proteins, based on 2DE immunoblotting, were predicted to be immunogenic. These included structural proteins actin, myosin and tubulin as well as certain moonlighting proteins (heat-shock chaperones) while enzymes with diverse catalytic activities were found as the most dominating group of proteins. In conclusion, the present study shed new light into the complexity of the enteric cestodiasis by showing that the H. diminuta somatic proteins exposed to the host possess immunomodulatory functions, and that the immune response of the host could be stimulated by diverse mechanisms, involving also those triggering protein export via yet unknown pathways.

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“…Currently, several strategies exist that can be applied to the identification of novel schistosomicidal lead compounds using VS methods. However, due the fact that schistosomiasis is a neglected tropical disease, the use of VS is still poorly explored, although some examples have appeared recently in the literature [ 139 , 140 , 141 , 142 ].…”

Section: Integration Of Natural Products and Virtual Screeningmentioning

confidence: 99%

Natural Products as Leads in Schistosome Drug Discovery

2015

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Schistosomiasis is a neglected parasitic tropical disease that claims around 200,000 human lives every year. Praziquantel (PZQ), the only drug recommended by the World Health Organization for the treatment and control of human schistosomiasis, is now facing the threat of drug resistance, indicating the urgent need for new effective compounds to treat this disease. Therefore, globally, there is renewed interest in natural products (NPs) as a starting point for drug discovery and development for schistosomiasis. Recent advances in genomics, proteomics, bioinformatics, and cheminformatics have brought about unprecedented opportunities for the rapid and more cost-effective discovery of new bioactive compounds against neglected tropical diseases. This review highlights the main contributions that NP drug discovery and development have made in the treatment of schistosomiasis and it discusses how integration with virtual screening (VS) strategies may contribute to accelerating the development of new schistosomidal leads, especially through the identification of unexplored, biologically active chemical scaffolds and structural optimization of NPs with previously established activity.

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3-Oxoacyl-ACP Reductase from Schistosoma japonicum: Integrated In Silico-In Vitro Strategy for Discovering Antischistosomal Lead Compounds

Cited by 16 publications

References 40 publications

Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis

Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis

Immunoproteomics and Surfaceomics of the Adult Tapeworm Hymenolepis diminuta

Natural Products as Leads in Schistosome Drug Discovery

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