Dataset Information

Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets.

ABSTRACT: Malaria, caused by protozoan of genus Plasmodium, remains one of the highest mortality infectious diseases. Malaria parasites have a complex life cycle, easily adapt to their host's immune system and have evolved with an arsenal of unique proteases which play crucial roles in proliferation and survival within the host cells. Owing to the existing knowledge of enzymatic mechanisms, 3D structures and active sites of proteases, they have been proven to be opportune for target based drug development. Here, we discuss in depth the crucial roles of essential proteases in Plasmodium life cycle and particularly focus on highlighting the atypical "structural signatures" of key parasite proteases which have been exploited for drug development. These features, on one hand aid parasites pathogenicity while on the other hand could be effective in designing targeted and very specific inhibitors for counteracting them. We conclude that Plasmodium proteases are suitable as multistage targets for designing novel drugs with new modes of action to combat malaria.

SUBMITTER: Mishra M

PROVIDER: S-EPMC6411711 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Structural Insights Into Key <i>Plasmodium</i> Proteases as Therapeutic Drug Targets.

Mishra Manasi M Singh Vigyasa V Singh Shailja S

Frontiers in microbiology 20190305

Malaria, caused by protozoan of genus <i>Plasmodium</i>, remains one of the highest mortality infectious diseases. Malaria parasites have a complex life cycle, easily adapt to their host's immune system and have evolved with an arsenal of unique proteases which play crucial roles in proliferation and survival within the host cells. Owing to the existing knowledge of enzymatic mechanisms, 3D structures and active sites of proteases, they have been proven to be opportune for target based drug deve ...[more]

PMID: 30891019

Similar Datasets

Project description:ObjectivePelvic organ prolapse (POP) is a disease in which pelvic floor support structures are dysfunctional due to disruption of the extracellular matrix (ECM). The vascular system is essential for maintaining ECM homeostasis. Therefore, this study explored the potential mechanism of blood vessel development-related genes (BVDRGs) in POP.MethodsPOP-related datasets and BVDRGs were included in this study. Differentially expressed genes (DEGs) between the POP and control groups were first identified in the GSE12852 and GSE208271 datasets, and DE-BVDRGs were identified by determining the intersection of these DEGs and BVDRGs. Subsequently, the feature genes were evaluated by machine learning. Feature genes with consistent expression trends in the GSE12852 and GSE208271 datasets were considered key genes. Afterward, the overall diagnostic efficacy of key genes in POP was evaluated through receiver operating characteristic (ROC) curve analysis. Based on the key genes, enrichment analysis, immune infiltration analysis and regulatory network construction were performed to elucidate the molecular mechanisms underlying the functions of the key genes in POP.ResultsA total of 888 DEGs1 and 643 DEGs2 were identified in the GSE12852 and GSE208271 datasets, and 26 candidate genes and 4 DE-BVDRGs were identified. Furthermore, Hyaluronan synthase 2 (HAS2), Matrix metalloproteinase 19 (MMP19) and Plexin Domain Containing 1 (PLXDC1) were identified as key genes in POP and had promising value for diagnosing POP (AUC > 0.8). Additional research revealed that the key genes were predominantly implicated in immune cell activation, chemotaxis, and cytokine release via the chemokine signaling pathway, the Nod-like receptor signaling pathway, and the Toll-like receptor signaling pathway. Analysis of immune cell infiltration confirmed a decrease in the proportion of plasma cells in POP, and MMP19 expression showed a significant negative correlation with plasma cell numbers. In addition, regulatory network analysis revealed that MALAT1 (a lncRNA) targeted hsa-miR-503-5p, hsa-miR-23a-3p and hsa-miR-129-5p to simultaneously regulate three key genes.ConclusionWe identified three key BVDRGs (HAS2, MMP19 and PLXDC1) related to the ECM in POP, providing markers for diagnostic studies and investigations of the molecular mechanism of POP.

Project description:Proteases and their inhibitors play critical roles in host-parasite interactions and in the outcomes of infections. Ceratonova shasta is a myxozoan pathogen that causes enteronecrosis in economically important salmonids from the Pacific Northwest of North America. This cnidarian parasite has host-specific genotypes with varying virulence, making it a powerful system to decipher virulence mechanisms in myxozoans. Using C. shasta genome and transcriptome, we identified four proteases of different catalytic types: cathepsin D (aspartic), cathepsin L and Z-like (cysteine) and aminopeptidase-N (metallo); and a stefin (cysteine protease inhibitor), which implied involvement in virulence and hence represent target molecules for the development of therapeutic strategies. We characterized, annotated and modelled their 3D protein structure using bioinformatics and computational tools. We quantified their expression in C. shasta genotype 0 (low virulence, no mortality) and IIR (high virulence and mortality) in rainbow trout Oncorhynchus mykiss, to demonstrate that there are major differences between the genotypes during infection and parasite development. High proliferation of genotype IIR was associated with high expression of the cathepsin D and the stefin, likely correlated with high nutrient demands and to regulate cell metabolism, with upregulation preceding massive proliferation and systemic dispersion. In contrast, upregulation of the cathepsin L and Z-like cysteine proteases may have roles in host immune evasion in genotype 0 infections, which are associated with low proliferation, low inflammation and non-destructive development. In contrast to the other proteases, C. shasta aminopeptidase-N appears to have a prominent role in nematocyst formation in both genotypes, but only during sporogenesis. Homology searches of C. shasta proteases against other myxozoan transcriptomes revealed a high abundance of cathepsin L and aminopeptidase homologs suggesting common gene requirements across species. Our study identified molecules of potential therapeutic significance for aquaculture and serves as a baseline for future research aimed at functional characterisation of these targets.

Dataset Information

Structural Insights Into Key Plasmodium Proteases as Therapeutic Drug Targets.

Publications

Structural Insights Into Key <i>Plasmodium</i> Proteases as Therapeutic Drug Targets.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets