Auto QSAR-based active learning docking for hit identification of potential inhibitors of Plasmodium falciparum Hsp90 as antimalarial agents.

Malaria which is mainly caused by Plasmodium falciparum parasite remains a devastating public health concern, necessitating the need to develop new antimalarial agents. P. falciparum heat shock protein 90 (Hsp90), is indispensable for parasite survival and a promising drug target.

A promising class of antiprotozoal agents, design and synthesis of novel Pyrimidine-Cinnamoyl hybrids.

Malaria, caused by parasitic protozoans of the Plasmodium genus, continues to be one of the greatest global health crises, especially in Africa. The emergence of antimalarial drug resistance continues to be a health problem necessitating an urgent need for alternative and cost-effective antimalarials. Using a molecular hybridization approach, we report the design and synthesis of an efficacious novel class of antiprotozoal agents; (E)-1-(4-(4,6-diphenylpyrimidin-2-yl)piperazin-1-yl)-3-phenyl prop-2-en-1-one derivatives (8a-r).

Swapping the linkers of canonical Hsp70 and Hsp110 chaperones compromises both self-association and client selection.

heat shock protein 70-1 (PfHsp70-1) and PfHsp70-z are essential cytosol localised chaperones of the malaria parasite. The two chaperones functionally interact to drive folding of several parasite proteins. While PfHsp70-1 is regarded as a canonical Hsp70 chaperone, PfHsp70-z belongs to the Hsp110 subcluster.

Escherichia coli-based Complementation Assay to Study the Chaperone Function of Heat Shock Protein 70.

Heat shock protein 70 (Hsp70) is a conserved protein that facilitates the folding of other proteins within the cell, making it a molecular chaperone. While Hsp70 is not essential for E. coli cells growing under normal conditions, this chaperone becomes indispensable for growth at elevated temperatures.

Plasmodium falciparum heat shock proteins as antimalarial drug targets: An update.

Global efforts to eradicate malaria are threatened by multiple factors, particularly the emergence of antimalarial drug resistant strains of Plasmodium falciparum. Heat shock proteins (HSPs), particularly P. falciparum HSPs (PfHSPs), represent promising drug targets due to their essential roles in parasite survival and virulence across the various life cycle stages.

Iso-mukaadial acetate and ursolic acid acetate bind to Plasmodium Falciparum heat shock protein 70: towards targeting parasite protein folding pathway.

Plasmodium falciparum is the most lethal malaria parasite. P. falciparum Hsp70 (PfHsp70) is an essential molecular chaperone (facilitates protein folding) and is deemed a prospective antimalarial drug target.

Correction: Bopape et al. The Genome of a Pigeonpea Compatible Rhizobial Strain '10ap3' Appears to Lack Common Nodulation Genes. 2023, , 1084.

was not included as an author in the original publication [...

Ursolic acid acetate and iso-mukaadial acetate bind to Plasmodium falciparum Hsp90, abrogating its chaperone function in vitro.

Plasmodium falciparum is the most lethal malaria parasite. Increasing incidences of drug resistance of P. falciparum have prompted the need for discovering new and effective antimalarial compounds with an alternative mode of action.

The multi-faceted roles of R2TP complex span across regulation of gene expression, translation, and protein functional assembly.

Macromolecular complexes play essential roles in various cellular processes. The assembly of macromolecular assemblies within the cell must overcome barriers imposed by a crowded cellular environment which is characterized by an estimated concentration of biological macromolecules amounting to 100-450 g/L that take up approximately 5-40% of the cytoplasmic volume. The formation of the macromolecular assemblies is facilitated by molecular chaperones in cooperation with their co-chaperones.

Insertion of GGMP repeat residues of Plasmodium falciparum Hsp70-1 in the lid of DnaK adversely impacts client recognition.

Although Hsp70 is a conserved molecular chaperone, it exhibits some degree of functional specialisation across species. Features of Hsp70 regulating its functional specialisation remain to be fully established. We previously demonstrated that E.

Pharmacophore Model-Based Virtual Screening Workflow for Discovery of Inhibitors Targeting Hsp90.

causes the most lethal and widespread form of malaria. Eradication of malaria remains a priority due to the increasing number of cases of drug resistance. The heat shock protein 90 of (PfHsp90) is a validated drug target essential for parasite survival.

2-Hydroxypropyl-β-cyclodextrin (HPβCD) as a Potential Therapeutic Agent for Breast Cancer.

Cholesterol accumulation is documented in various malignancies including breast cancer. Consequently, depleting cholesterol in cancer cells can serve as a viable treatment strategy. We identified the potency of 2-hydroxypropyl-β-cyclodextrin (HPβCD), a cholesterol-depletor in vitro against two breast cancer cell lines: MCF-7 (Oestrogen-receptor positive, ER+) and MDA-MB-231 (Triple negative breast cancer (TNBC)).

The Genome of a Pigeonpea Compatible Rhizobial Strain '10ap3' Appears to Lack Common Nodulation Genes.

The symbiotic fixation of atmospheric nitrogen (N) in root nodules of tropical legumes such as pigeonpea () is a complex process, which is regulated by multiple genetic factors at the host plant genotype microsymbiont interface. The process involves multiple genes with various modes of action and is accomplished only when both organisms are compatible. Therefore, it is necessary to develop tools for the genetic manipulation of the host or bacterium towards improving N fixation.

Human granzyme B binds Plasmodium falciparum Hsp70-x and mediates antiplasmodial activity in vitro.

Cell surface-bound human Hsp70 (hHsp70) sensitises tumour cells to the cytolytic attack of natural killer (NK) cells through the mediation of apoptosis-inducing serine protease, granzyme B (GrB). hHsp70 is thought to recruit NK cells to the immunological synapse via the extracellularly exposed 14 amino acid sequence, TKDNNLLGRFELSG, known as the TKD motif of Hsp70. Plasmodium falciparum-infected red blood cells (RBCs) habour both hHsp70 and an exported parasite Hsp70 termed PfHsp70-x.

Inhibition of Hsp70-Hop partnership by 2-phenylthynesulfonamide.

Hsp70-1 (PfHsp70-1; PF3D7_0818900) and PfHsp90 (PF3D7_0708400) are essential cytosol localized chaperones of the malaria parasite. The two chaperones form a functional complex via the adaptor protein, Hsp90-Hsp70 organizing protein (PfHop [PF3D7_1434300]), which modulates the interaction of PfHsp70-1 and PfHsp90 through its tetracopeptide repeat (TPR) domains in a nucleotide-dependent fashion. On the other hand, PfHsp70-1 and PfHsp90 possess C-terminal EEVD and MEEVD motifs, respectively, which are crucial for their interaction with PfHop.

Host cell stress response as a predictor of COVID-19 infectivity and disease progression.

The coronavirus disease (COVID-19) caused by a coronavirus identified in December 2019 has caused a global pandemic. COVID-19 was declared a pandemic in March 2020 and has led to more than 6.3 million deaths.

Heat Shock Proteins of Malaria: Highlights and Future Prospects.

The deadliest malaria parasite of humans, Plasmodium falciparum, is an obligate parasite that has had to develop mechanisms for survival under the unfavourable conditions it confronts within host cells. The chapters in the book "Heat Shock Proteins of Malaria" provide a critique of the evidence that heat shock proteins (Hsps) play a key role in the survival of P. falciparum in host cells.

Bioprospecting for Novel Heat Shock Protein Modulators: The New Frontier for Antimalarial Drug Discovery?

Heat shock proteins are conserved molecules whose main role is to facilitate protein folding. However, they are also implicated in protein trafficking, protein assembly/disassembly, and functional maturation of proteins implicated in several biochemical pathways, including signal transduction. The role of heat shock proteins in the development of malaria parasites has recently become a subject of enormous interest.

The Role of Hsp70s in the Development and Pathogenicity of Plasmodium falciparum.

The main agent of human malaria, the protozoa, Plasmodium falciparum is known to infect liver cells, subsequently invading the host erythrocyte, leading to the manifestation of clinical outcomes of the disease. As part of its survival in the human host, P. falciparum employs several heat shock protein (Hsp) families whose primary purpose is to ensure cytoprotection through their molecular chaperone role.

Heat Shock Proteins: Potential Modulators and Candidate Biomarkers of Peripartum Cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. To date, no reliable biomarkers or therapeutic interventions for the condition exist, thus necessitating an urgent need for identification of novel PPCM drug targets and candidate biomarkers. Leads for novel treatments and biomarkers are therefore being investigated worldwide.

Characterization of an Atypical Hsp70 Demonstrates Its Cytosolic-Nuclear Localization and Modulation by Quercetin and Methylene Blue.

(Tb) harbours twelve Hsp70 chaperones. Of these, four are predicted to reside in the parasite cytosol. TbHsp70.

Supporting data on characterisation of linker switch mutants of heat shock protein 110 and canonical Hsp70.

Here, we present data on characterisation of the linker of Hsp110 (PfHsp70-z) relative to the linker of canonical Hsp70s in support of a co-published article [1]. The linker of PfHsp70-z was switched with that of canonical Hsp70s, represented by PfHsp70-1 (cytosolic counterpart of PfHsp70-z) and Hsp70/DnaK. The datasets represent comparative analyses of PfHsp70-z, PfHsp70-1, and DnaK, relative to their linker switch mutants; PfHsp70-z, PfHsp70-1, DnaK, respectively.

'Meet the editor series'-Addmore Shonhai.

It gives me great pleasure to have the opportunity to introduce myself to the readers of Biophysical Reviews as part of the 'meet the editors' series. What follows is a mini-autobiography of my life as it relates to my scientific career and research.

Design and synthesis of quinoline-pyrimidine inspired hybrids as potential plasmodial inhibitors.

Presently, artemisinin-based combination therapy (ACT) is the first-line therapy of Plasmodium falciparum malaria. With the emergence of malaria parasites that are resistant to ACT, alternative antimalarial therapies are urgently needed. In line with this, we designed and synthesised a series of novel N-(7-chloroquinolin-4-yl)-N'-(4,6-diphenylpyrimidin-2-yl)alkanediamine hybrids (6a-7c) and evaluated their inhibitory activity against the NF54 chloroquine-susceptible strain as a promising class of antimalarial compounds.

Characterisation of a unique linker segment of the Plasmodium falciparum cytosol localised Hsp110 chaperone.

Plasmodium falciparum expresses two essential cytosol localised chaperones; PfHsp70-1 and PfHsp70-z. PfHsp70-z (Hsp110 homologue) is thought to facilitate nucleotide exchange function of PfHsp70-1. PfHsp70-1 is a refoldase, while PfHsp70-z is restricted to holdase chaperone function.