Screening the medicines for Malaria Venture "Malaria Box" against the Plasmodium falciparum aminopeptidases, M1, M17 and M18

Malaria is a parasitic disease that remains a global health burden. The ability of the parasite to rapidly develop resistance to therapeutics drives an urgent need for the delivery of new drugs. The Medicines for Malaria Venture have compounds known for their antimalarial ac- tivity, but not necessarily the molecular targets. In this study, we assess the ability of the “MMV 400” compounds to inhibit the activity of three metalloaminopeptidases from Plasmo- dium falciparum, PfA-M1, PfA-M17 and PfM18 AAP. We have developed a multiplex assay system to allow rapid primary screening of compounds against all three metalloaminopepti- dases, followed by detailed analysis of promising compounds. Our results show that there were no PfM18AAP inhibitors, whereas two moderate inhibitors of the neutral aminopepti- dases PfA-M1 and PfA-M17 were identified. Further investigation through structure-activity relationship studies and molecular docking suggest that these compounds are competitive inhibitors with novel binding mechanisms, acting through either non-classical zinc coordina- tion or independently of zinc binding altogether. Although it is unlikely that inhibition of PfA- M1 and/or PfA-M17 is the primary mechanism responsible for the antiplasmodial activity re- ported for these compounds, their detailed characterization, as presented in this work, pave the way for their further optimization as a novel class of dual PfA-M1/PfA-M17 inhibitors uti- lising non-classical zinc binding groups

Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum

Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment

Soils of India: historical perspective, classification and recent advances

Derived from a wide range of rocks and minerals, a large variety of soils occur in the Indian subcontinent. Soil-forming factors like climate, vegetation and topography acting for varying periods on a range of rock formations and parent materials, have given rise to different kinds of soil. The National Bureau of Soil Survey and Land Use Planning, Nagpur has developed a database on soils with field and laboratory studies over the last 30 years. This has generated maps and soil information at different scales, showing area and distribution of various soil groups in different agroecological subregions. The 1 : 250,000 scale map shows a threshold soil variation index of 4–5 and 10–25 soil families per m ha for alluvial plains and black soil regions respectively. Progress in basic and fundamental research in Indian soils has been reviewed in terms of soils, their formation related to climate, relief, organisms, parent materials and time

Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics

Soil information system: use and potentials in humid and semi-arid tropics

The articles presented in this special section emanated from the researches of consortium members of the National Agricultural Innovative Project (NAIP, Component 4) of the Indian Council of Agricultural Research (ICAR), New Delhi. These researches have helped develop a soil information system (SIS). In view of the changing scenario all over the world, the need of the hour is to get assistance from a host of researchers specialized in soils, crops, geology, geography and information technology to make proper use of the datasets. Equipped with the essential knowledge of data storage and retrieval for management recommendations, these experts should be able to address the issues of land degradation, biodiversity, food security, climate change and ultimately arrive at an appropriate agricultural land-use planning. Moreover, as the natural resource information is an essential prerequisite for monitoring and predicting global environmental change with special reference to climate and land use options, the SIS needs to be a dynamic exercise to accommodate temporal datasets, so that subsequently it should result in the evolution of the soil information technology. The database developed through this NAIP would serve as an example of the usefulness of the Consortium and the research initiative of ICAR involving experts from different fields to find out the potentials of the soils of humid and semi-arid bioclimatic systems of the country

Georeferenced soil information system: assessment of database

Land-use planning is a decision-making process that facilitates the allocation of land to different uses that provide optimal and sustainable benefit. As land-use is shaped by society–nature interaction, in land-use planning different components/facets play a significant role involving soil, water, climate, animal (ruminant/ non-ruminant) and others, including forestry and the environment needed for survival of mankind. At times these components are moderated by human interference. Thus land-use planning being a dynamic phenomenon is not guided by a single factor, but by a complex system working simultaneously,which largely affects the sustainability. To address such issues a National Agricultural Innovation Project (NAIP) on ‘Georeferenced soil information system for land-use planning and monitoring soil and land quality for agriculture’ was undertaken to develop threshold values of land quality parameters for land-use planning through quantitative land evaluation and crop modelling for dominant cropping systems in major agro-ecological sub-regions (AESRs) representing rice–wheat cropping system in the Indo-Gangetic Plains (IGP) and deep-rooted crops in the black soil regions (BSR). To assess the impact of landuse change, threshold land quality indicator values are used. A modified AESR map for agricultural landuse planning is generated for effective land-use planning

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Not AvailableAIMS: Establishment of inoculated biofilms on root surfaces and their effect on plant enzyme activities and nutrient availability in the rhizosphere are less investigated. Two beneficial inoculants- Trichoderma spp. and Azotobacter spp., and the biofilm developed using them as partners, were evaluated in chickpea crop. The hypothesis tested was that the efficacy of the fungal-based bacterial biofilm in colonizing the root and rhizosphere may be better, as compared to their individual inoculation. METHODS: Scanning electron microscopy and root staining illustrated the colonisation of developed T. viride (Tv) – A. chroococcum (Az) biofilm and their partners. Inoculation effects were analysed on selected plant growth parameters, soil nutrients, plant enzyme activities and organic acid exudations in the rhizosphere soil. RESULTS: Tv-Az biofilm was observed to exhibit better colonization in the rhizosphere and rhizoplane of chickpea, as compared to single inoculation. Significant enhancement of 30–45% in root volume, root proteins, root-shoot ratio, exudation of succinic and fumaric acids, soil available nutrients, along with two fold enhancement in the activity of plant enzymes was recorded, as compared to recommended doses of NPK fertilizers. CONCLUSIONS: Tv-Az biofilm is a promising biofertilizing option for enhancing plant growth parameters, available soil nutrients, along with providing a savings of 25% nitrogenous fertilizers in chickpea.Not Availabl

Synthesis and evaluation of an acyl-chain unsaturated analog of the Th2 biasing, immunostimulatory glycolipid, OCH

An α-galactosyl ceramide (α-GalCer) 2 was synthesized and evaluated for its ability to stimulate iNKT-cell proliferation and elicit T-helper cytokines, IL-4 and IFNγ. Compound 2 combines the acyl chain of the potent, Th2 biasing α-GalCer 1 with a sphingoid base of the same length as that found in OCH, which also exhibits Th2 skewing, Such complementation may enhance cytokine bias, which is thought to be important for therapeutic applications of iNKT cell stimulation. Two related α-GalCers, 3 and 4, with saturated acyl chains were prepared for comparison

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Not AvailableMicrobial biofilms are gaining importance in agriculture, due to their multifaceted agronomic benefits and resilience to environmental fluctuations. This study focuses on comparing the influence of single inoculation-Azotobacter chroococcum (Az) or Trichoderma viride (Tv) and their biofilm (Tv-Az), on soil and plant metabolic activities in wheat and cotton grown under Phytotron conditions. Tv-Az proved superior to all the other treatments in terms of better colonisation, plant growth attributes and 10-40% enhanced availability of macronutrients and micronutrients in the soil, over control. Confocal and scanning electron microscopy showed that the cells attached to the root tips initially, followed by their proliferation along the surface of the roots. Soil polysaccharides, proteins and dehydrogenase activity showed several fold enhancement in Tv-Az biofilm inoculated samples. Time course studies revealed that the population of Az and Tv in the rhizoplane and rhizosphere was significantly higher with a 0.14-0.31 log colony-forming unit (CFU) increase in the biofilm-inoculated treatment in both crops. Enhancement in soil biological activities was facilitated by the improved colonisation of the biofilm, due to the synergistic association between Tv and Az. This demonstrates the utility of Tv-Az biofilm as a multifunctional plant growth promoting and soil fertility enhancing option in agriculture.Not Availabl