Inhibitors of malaria parasite cyclic nucleotide phosphodiesterases block asexual blood-stage development and mosquito transmission.

Cyclic nucleotide-dependent phosphodiesterases (PDEs) play essential roles in regulating the malaria parasite life cycle, suggesting that they may be promising antimalarial drug targets. PDE inhibitors are used safely to treat a range of noninfectious human disorders. Here, we report three subseries of fast-acting and potent PDEβ inhibitors that block asexual blood-stage parasite development and that are also active against human clinical isolates.

Identification of the drug/metabolite transporter 1 as a marker of quinine resistance in a NF54×Cam3.II genetic cross.

The genetic basis of resistance to quinine (QN), a drug used to treat severe malaria, has long been enigmatic. To gain further insight, we used FRG-NOD human liver-chimeric mice to conduct a genetic cross between QN-sensitive and QN-resistant parasites, which also differ in their susceptibility to chloroquine (CQ). By applying different selective conditions to progeny pools prior to cloning, we recovered 120 unique recombinant progeny.

Mixed alkyl/aryl phosphonates identify metabolic serine hydrolases as antimalarial targets.

Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial drugs is the ability of the parasite to rapidly generate resistance. We previously demonstrated that salinipostin A (SalA), a natural product, potently kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism that results in a low propensity for resistance.

A Micronemal Protein, Scot1, Is Essential for Apicoplast Biogenesis and Liver Stage Development in .

sporozoites invade hepatocytes, transform into liver stages, and replicate into thousands of merozoites that infect erythrocytes and cause malaria. Proteins secreted from micronemes play an essential role in hepatocyte invasion, and unneeded micronemes are subsequently discarded for replication. The liver-stage parasites are potent immunogens that prevent malarial infection.

The novel Plasmodium berghei protein S14 is essential for sporozoite gliding motility and infectivity.

Plasmodium sporozoites are the infective forms of the malaria parasite in the mosquito and vertebrate host. Gliding motility allows sporozoites to migrate and invade mosquito salivary glands and mammalian hosts. Motility and invasion are powered by an actin-myosin motor complex linked to the glideosome, which contains glideosome-associated proteins (GAPs), MyoA and the myosin A tail-interacting protein (MTIP).

Stearoyl-CoA desaturase regulates organelle biogenesis and hepatic merozoite formation in Plasmodium berghei.

Plasmodium is an obligate intracellular parasite that requires intense lipid synthesis for membrane biogenesis and survival. One of the principal membrane components is oleic acid, which is needed to maintain the membrane's biophysical properties and fluidity. The malaria parasite can modify fatty acids, and stearoyl-CoA Δ9-desaturase (Scd) is an enzyme that catalyzes the synthesis of oleic acid by desaturation of stearic acid.

Mixed Alkyl/Aryl Phosphonates Identify Metabolic Serine Hydrolases as Antimalarial Targets.

Malaria, caused by remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, kills parasites by inhibiting multiple lipid metabolizing serine hydrolases, a mechanism with a low propensity for resistance.

Protein kinase 9 is not required for completion of the Plasmodium berghei life cycle.

Protein kinases uniquely expressed in Plasmodium represent attractive drug targets. Previous studies have reported that Plasmodium falciparum Protein kinase 9 (Pk9) phosphorylates regulatory serine 106 of the ubiquitin-conjugating enzyme (Ubc13) thereby negatively regulating its activity. We investigated the effect of Pk9 depletion and Ubc13 mutation at S106 on the progression of rodent malaria model P.

Mitochondrial apurinic/apyrimidinic endonuclease Apn1 is not critical for the completion of the Plasmodium berghei life cycle.

Mitochondrion is an essential organelle in malaria parasite and its DNA must be maintained for optimal function during its complex life cycle. Base excision repair is one of the major pathways by which this is achieved. Apurinic/apyrimidinic (AP) endonucleases are important components of this pathway as they create a nick at the 5'-phosphodiester bond in the AP site and generate free 5'-phosphate and 3'-hydroxyl groups.

Secreted protein with altered thrombospondin repeat (SPATR) is essential for asexual blood stages but not required for hepatocyte invasion by the malaria parasite Plasmodium berghei.

Upon entering its mammalian host, the malaria parasite productively invades two distinct cell types, that is, hepatocytes and erythrocytes during which several adhesins/invasins are thought to be involved. Many surface-located proteins containing thrombospondin Type I repeat (TSR) which help establish host-parasite molecular crosstalk have been shown to be essential for mammalian infection. Previous reports indicated that antibodies produced against Plasmodium falciparum secreted protein with altered thrombospondin repeat (SPATR) block hepatocyte invasion by sporozoites but no genetic evidence of its contribution to invasion has been reported.

A putative serine-threonine kinase 2 () is required for late liver stage development and timely initiation of blood stage infection.

In , protein kinases govern key biological processes of the parasite life cycle involved in the establishment of infection, dissemination and sexual reproduction. The rodent malaria model encodes for 66 putative eukaryotic protein kinases (ePKs) as identified through modelling domain signatures and are highly conserved in We report here the functional characterisation of a putative serine-threonine kinase identified in this kinome analysis and designate it as To elucidate its role, we knocked out locus and performed a detailed phenotypic analysis at different life cycle stages. The knockout (KO) was not compromised in asexual blood stage propagation, transmission and development in the mosquito vector.

Plasmodium berghei plasmepsin VIII is essential for sporozoite gliding motility.

Plasmodium aspartic proteases, termed plasmepsins (PMs) play many critical roles such as haemoglobin degradation, cleavage of PEXEL proteins and sporozoite development in the parasite life cycle. Most of the plasmepsins are well characterized, however the role of PM VIII in Plasmodium remains unknown. Here, we elucidate the functions of PM VIII (PBANKA_132910) in the rodent malaria parasite Plasmodium berghei (Pb).

Lipases in Medicine: An Overview.

Lipases are part of the family of hydrolases that act on carboxylic ester bonds. They are involved in catalyzing the hydrolysis of triglycerides (TG) into chylomicrons and very low density lipoprotein (VLDL) particles. Uses of lipases are evolving rapidly and currently they are reported to show high potential in medicine.

Production and characterization of biodiesel using nonedible castor oil by immobilized lipase from Bacillus aerius.

A novel thermotolerant lipase from Bacillus aerius was immobilized on inexpensive silica gel matrix. The immobilized lipase was used for the synthesis of biodiesel using castor oil as a substrate in a solvent free system at 55°C under shaking in a chemical reactor. Several crucial parameters affecting biodiesel yield such as incubation time, temperature, substrate molar ratio, and amount of lipase were optimized.

Comparative study of free and immobilized lipase from Bacillus aerius and its application in synthesis of ethyl ferulate.

In the present study, a purified lipase from Bacillus aerius immobilized on celite matrix was used for synthesis of ethyl ferulate. The celite-bound lipase exposed to glutaraldehyde showed 90.02% binding efficiency.

Characterization and catalytic properties of free and silica-bound lipase: a comparative study.

In the present study, the commercial lipase from Himedia, Mumbai was immobilized on silica gel matrix in the presence of a cross-linking agent, glutaraldehyde. The silica immobilized lipase exposed to 2% glutaraldehyde showed 94.28% binding efficiency.

Biodiesel production by transesterification using immobilized lipase.

Biodiesel can be produced by transesterification of vegetable or waste oil catalysed by lipases. Biodiesel is an alternative energy source to conventional fuel. It combines environmental friendliness with biodegradability, low toxicity and renewability.