Plasmodium falciparum contains functional SCF and CRL4 ubiquitin E3 ligases, and CRL4 is critical for cell division and membrane integrity.

Protein ubiquitination is essential for cellular homeostasis and regulation of several processes, including cell division and genome integrity. Ubiquitin E3 ligases determine substrate specificity for ubiquitination, and Cullin-RING E3 ubiquitin ligases (CRLs) make the largest group among the ubiquitin E3 ligases. Although conserved and most studied in model eukaryotes, CRLs remain underappreciated in Plasmodium and related parasites.

Development of diphenylmethylpiperazine hybrids of chloroquinoline and triazolopyrimidine using Petasis reaction as new cysteine proteases inhibitors for malaria therapeutics.

Malaria is a widespread infectious disease, causing nearly 247 million cases in 2021. The absence of a broadly effective vaccine and rapidly decreasing effectiveness of most of the currently used antimalarials are the major challenges to malaria eradication efforts. To design and develop novel antimalarials, we synthesized a series of 4,7-dichloroquinoline and methyltriazolopyrimidine analogues using a multi-component Petasis reaction.

A comparative study of antibody response, virus neutralization efficiency & metabolites in SARS-CoV-2-infected adults & children.

Background & Objectives: COVID-19 has been a global pandemic since early 2020. It has diverse clinical manifestations, but consistent immunological and metabolic correlates of disease severity and protection are not clear. This study was undertaken to compare seropositivity rate, antibody levels against nucleocapsid and spike proteins, virus neutralization and metabolites between adult and child COVID-19 patients.

Plasmodium DDI1 is a potential therapeutic target and important chromatin-associated protein.

DNA damage inducible 1 protein (DDI1) is involved in a variety of cellular processes including proteasomal degradation of specific proteins. All DDI1 proteins contain a ubiquitin-like (UBL) domain and a retroviral protease (RVP) domain. Some DDI1 proteins also contain a ubiquitin-associated (UBA) domain.

Bazedoxifene, a Postmenopausal Drug, Acts as an Antimalarial and Inhibits Hemozoin Formation.

Despite a remarkable improvement in health care and continued drug discovery efforts, malaria control efforts are continuously challenged by the emergence of drug-resistant parasite strains. Given a long and risky development path of new drugs, repurposing existing drugs for the treatment of malaria is an attractive and shorter path. Tamoxifen, a selective estrogen receptor modulator (SERM) for the treatment and prevention of estrogen receptor-positive breast cancer, possesses antibacterial, antifungal, and antiparasitic activities.

Dissecting Pathobiology: Proteomic Approaches for Decoding Novel Translational and Post-Translational Modifications.

Malaria is a vector-borne disease. It is caused by parasites. is a rodent model parasite, primarily used for studying parasite development in liver cells and vectors.

Plasmodium falciparum Atg18 localizes to the food vacuole via interaction with the multi-drug resistance protein 1 and phosphatidylinositol 3-phosphate.

Autophagy, a lysosome-dependent degradative process, does not appear to be a major degradative process in malaria parasites and has a limited repertoire of genes. To better understand the autophagy process, we investigated Plasmodium falciparum Atg18 (PfAtg18), a PROPPIN family protein, whose members like S. cerevisiae Atg18 (ScAtg18) and human WIPI2 bind PI3P and play an essential role in autophagosome formation.

Characterization of Plasmodium falciparum NEDD8 and identification of cullins as its substrates.

A variety of post-translational modifications of Plasmodium falciparum proteins, including phosphorylation and ubiquitination, are shown to have key regulatory roles during parasite development. NEDD8 is a ubiquitin-like modifier of cullin-RING E3 ubiquitin ligases, which regulates diverse cellular processes. Although neddylation is conserved in eukaryotes, it is yet to be characterized in Plasmodium and related apicomplexan parasites.

Lyse-Reseal Erythrocytes for Transfection of Plasmodium falciparum.

Simple and efficient transfection methods for genetic manipulation of Plasmodium falciparum are desirable to identify, characterize and validate the genes with therapeutic potential and better understand parasite biology. Among the available transfection techniques for P. falciparum, electroporation-based methods, particularly electroporation of ring-infected RBCs is routinely used.

GCN5 acetyltransferase follows a novel proteolytic processing pathway that is essential for its function.

The pathogenesis of human malarial parasite is interlinked with its timely control of gene expression during its complex life cycle. In this organism, gene expression is partially controlled through epigenetic mechanisms, the regulation of which is, hence, of paramount importance to the parasite. The (Pf)-GCN5 histone acetyltransferase (HAT), an essential enzyme, acetylates histone 3 and regulates global gene expression in the parasite.

Identification of antimalarial leads with dual falcipain-2 and falcipain-3 inhibitory activity.

Falcipains (FPs), cysteine proteases in the malarial parasite, are emerging as the promising antimalarial drug targets. In order to identify novel FP inhibitors, we generated a pharmacophore derived from the reported co-crystal structures of inhibitors of Plasmodium falciparum Falcipain-3 to screen the ZINC library. Further, the filters were applied for dock score, drug-like characters, and clustering of similar structures.

Interaction with complement proteins and dendritic cells implicates LCCL domain-containing proteins (CCps) of malaria parasites in immunomodulation.

The evasion of host immune defense is critical for pathogens to invade, establish infection and perpetuate in the host. The complement system is one of the first lines of innate immune defense in humans that destroys pathogens in the blood circulation. Activation of the complement system through direct encounter with pathogens or some other agents leads to osmolysis of pathogens, clearance of soluble immune complexes and recruitment of lymphocytes at the site of activation.

Biotransformation of Artemisinin to 14-Hydroxydeoxyartemisinin: C-14 Hydroxylation by Aspergillus flavus.

The biotransformation of the front-line antimalarial drug, artemisinin (1) by the filamentous fungus Aspergillus flavus MTCC-9167 was investigated. Incubation of compound 1 with A. flavus afforded a new hydroxy derivative (2) along with three known metabolites (3-5).

A conserved human DJ1-subfamily motif (DJSM) is critical for anti-oxidative and deglycase activities of Plasmodium falciparum DJ1.

Plasmodium falciparum DJ1 (PfDJ1) belongs to the DJ-1/ThiJ/PfpI superfamily whose members are present in all the kingdoms of life and exhibit diverse cellular functions and biochemical activities. The common feature of the superfamily is the class I glutamine amidotransferase domain with a conserved redox-active cysteine residue, which mediates various activities of the superfamily members, including anti-oxidative activity in PfDJ1 and human DJ1 (hDJ1). As the superfamily members represent diverse functional classes, to investigate if there is any sequence feature unique to hDJ1-like proteins, sequences of the representative proteins of different functional classes were compared and analysed.

Synthesis and evaluation of anti-plasmodial and cytotoxic activities of epoxyazadiradione derivatives.

Epoxyazadiradione (1), a major compound derived from Neem oil, showed modest anti-plasmodial activity against CQ-resistant and CQ-sensitive strains of the most virulent human malaria parasite P. falciparum. A series of analogues were synthesized by modification of the key structural moieties of this high yield natural product.

A Novel and Conserved Plasmodium Sporozoite Membrane Protein SPELD is Required for Maturation of Exo-erythrocytic Forms.

Plasmodium sporozoites are the infective forms of malaria parasite to vertebrate host and undergo dramatic changes in their transcriptional repertoire during maturation in mosquito salivary glands. We report here the role of a novel and conserved Plasmodium berghei protein encoded by PBANKA_091090 in maturation of Exo-erythrocytic Forms (EEFs) and designate it as Sporozoite surface Protein Essential for Liver stage Development (PbSPELD). PBANKA_091090 was previously annotated as PB402615.

Synthesis and evaluation of naphthyl bearing 1,2,3-triazole analogs as antiplasmodial agents, cytotoxicity and docking studies.

Novel series of naphthyl bearing 1,2,3-triazoles (4a-t) were synthesized and evaluated for their in vitro antiplasmodial activity against pyrimethamine (Pyr)-sensitive and resistant strains of Plasmodium falciparum. The synthesized compounds were assessed for their cytotoxicity employing human embryonic kidney cell line (HEK-293), and none of them was found to be toxic. Among them 4j, 4k, 4l, 4m, 4n, 4t exhibited significant antiplasmodial activity in both strains, of which compounds 4m, 4n and 4t (∼3.

Independent amino acid residues in the S2 pocket of falcipain-3 determine its specificity for P2 residues in substrates.

Falcipain-3 (FP3) is an essential and drug target cysteine protease of the most lethal human malaria parasite Plasmodium falciparum. FP3 and its majority of homologs in malaria parasites prefer Leu at the P2 position in substrates and inhibitors, whereas its major host homolog cathepsin L prefers Phe. However, FP3 is much less active on peptide substrates and has negligible activity against a P2 Arg-containing substrate (Z-RR-AMC) compared to its paralog falcipain-2A (FP2A).

Characterization of the autophagy marker protein Atg8 reveals atypical features of autophagy in Plasmodium falciparum.

Conventional autophagy is a lysosome-dependent degradation process that has crucial homeostatic and regulatory functions in eukaryotic organisms. As malaria parasites must dispose a number of self and host cellular contents, we investigated if autophagy in malaria parasites is similar to the conventional autophagy. Genome wide analysis revealed a partial autophagy repertoire in Plasmodium, as homologs for only 15 of the 33 yeast autophagy proteins could be identified, including the autophagy marker Atg8.

Genetic ablation of plasmoDJ1, a multi-activity enzyme, attenuates parasite virulence and reduces oocyst production.

Malaria parasites must respond to stresses and environmental signals to perpetuate efficiently during their multistage development in diverse environments. To gain insights into the parasite's stress response mechanisms, we investigated a conserved Plasmodium protein, which we have named plasmoDJ1 on the basis of the presence of a putative cysteine protease motif of the DJ-1/PfpI superfamily, for its activities, potential to respond to stresses and role in parasite development. PlasmoDJ1 is expressed in all intraerythrocytic stages and ookinetes.

Genetic ablation of plasmoDJ1, a multi-activity enzyme, attenuates parasite virulence and reduces oocyst production.

Malaria parasites must respond to stresses and environmental signals to perpetuate efficiently during their multistage development in diverse environments. To gain insights into the parasite's stress response mechanisms, we investigated a conserved Plasmodium protein, which we have named plasmoDJ1 on the basis of the presence of a putative cysteine protease motif of the DJ-1/PfpI superfamily, for its activities, potential to respond to stresses and role in parasite development. PlasmoDJ1 is expressed in all intraerythrocytic stages and ookinetes.

Emergence of pyrido quinoxalines as new family of antimalarial agents.

A series of novel N-alkyl dihydro pyrido quinoxaline derivatives were synthesized using Gould-Jacobs reaction and evaluated their antimalarial activity in vitro against chloroquine sensitive (3D7) and drug resistant (Dd2) strains of Plasmodium falciparum. Among the compounds tested, 10 compounds were more potent than their structural standard analog ciprofloxacin, including 2 derivatives 5e and 5h, which showed 3.3-7.

Blocking Plasmodium falciparum development via dual inhibition of hemoglobin degradation and the ubiquitin proteasome system by MG132.

Among key potential drug target proteolytic systems in the malaria parasite Plasmodium falciparum are falcipains, a family of hemoglobin-degrading cysteine proteases, and the ubiquitin proteasomal system (UPS), which has fundamental importance in cellular protein turnover. Inhibition of falcipains blocks parasite development, primarily due to inhibition of hemoglobin degradation that serves as a source of amino acids for parasite growth. Falcipains prefer P2 leucine in substrates and peptides, and their peptidyl inhibitors with leucine at the P2 position show potent antimalarial activity.