An experimental target-based platform in yeast for screening Plasmodium vivax deoxyhypusine synthase inhibitors.

The enzyme deoxyhypusine synthase (DHS) catalyzes the first step in the post-translational modification of the eukaryotic translation factor 5A (eIF5A). This is the only protein known to contain the amino acid hypusine, which results from this modification. Both eIF5A and DHS are essential for cell viability in eukaryotes, and inhibiting DHS is a promising strategy to develop new therapeutic alternatives.

A novel 4-aminoquinoline chemotype with multistage antimalarial activity and lack of cross-resistance with PfCRT and PfMDR1 mutants.

Artemisinin-based combination therapy (ACT) is the mainstay of effective treatment of Plasmodium falciparum malaria. However, the long-term utility of ACTs is imperiled by widespread partial artemisinin resistance in Southeast Asia and its recent emergence in parts of East Africa. This underscores the need to identify chemotypes with new modes of action (MoAs) to circumvent resistance to ACTs.

An automated positive selection screen in yeast provides support for boron-containing compounds as inhibitors of SARS-CoV-2 main protease.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus continues to cause severe disease and deaths in many parts of the world, despite massive vaccination efforts. Antiviral drugs to curb an ongoing infection remain a priority. The virus-encoded 3C-like main protease (MPro; nsp5) is seen as a promising target.

Truncating the spliceosomal 'rope protein' Prp45 results in Htz1 dependent phenotypes.

Spliceosome assembly contributes an important but incompletely understood aspect of splicing regulation. Prp45 is a yeast splicing factor which runs as an extended fold through the spliceosome, and which may be important for bringing its components together. We performed a whole genome analysis of the genetic interaction network of the truncated allele of ((1-169)) using synthetic genetic array technology and found chromatin remodellers and modifiers as an enriched category.

Exploring Subsite Selectivity within -Myristoyltransferase Using Pyrazole-Derived Inhibitors.

-myristoyltransferase (NMT) is a promising antimalarial drug target. Despite biochemical similarities between and human NMTs, our recent research demonstrated that high selectivity is achievable. Herein, we report NMT-inhibiting compounds aimed at identifying novel mechanisms of selectivity.

Selective Bias Virtual Screening for Discovery of Promising Antimalarial Candidates targeting Plasmodium N-Myristoyltransferase.

Malaria remains a significant public health challenge, with being the species responsible for the most prevalent form of the disease. Given the limited therapeutic options available, the search for new antimalarials against is urgent. This study aims to identify new inhibitors for -myristoyltransferase (PvNMT), an essential drug target against malaria.

α-Aminophosphonate inhibitors of metallo-β-lactamases NDM-1 and VIM-2.

The upswing of antibiotic resistance is an escalating threat to human health. Resistance mediated by bacterial metallo-β-lactamases is of particular concern as these enzymes degrade β-lactams, our most frequently prescribed class of antibiotics. Inhibition of metallo-β-lactamases could allow the continued use of existing β-lactam antibiotics, such as penicillins, cephalosporins and carbapenems, whose applicability is becoming ever more limited.

Identification of potential inhibitors of casein kinase 2 alpha of with potent activity.

Drug resistance to commercially available antimalarials is a major obstacle in malaria control and elimination, creating the need to find new antiparasitic compounds with novel mechanisms of action. The success of kinase inhibitors for oncological treatments has paved the way for the exploitation of protein kinases as drug targets in various diseases, including malaria. Casein kinases are ubiquitous serine/threonine kinases involved in a wide range of cellular processes such as mitotic checkpoint signaling, DNA damage response, and circadian rhythm.

Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts.

Drugs targeting multiple stages of the Plasmodium vivax life cycle are needed to reduce the health and economic burdens caused by malaria worldwide. N-myristoyltransferase (NMT) is an essential eukaryotic enzyme and a validated drug target for combating malaria. However, previous PvNMT inhibitors have failed due to their low selectivity over human NMTs.

Crotofolane Diterpenoids and Other Constituents Isolated from .

Six new crotofolane diterpenoids (-) and 13 known compounds (-) were isolated from the MeOH-CHCl (1:1, v/v) extracts of the leaves and stem bark of . The structures of the new compounds were elucidated by extensive analysis of spectroscopic and mass spectrometric data. The structure of crotokilwaepoxide A () was confirmed by single-crystal X-ray diffraction, allowing for the determination of its absolute configuration.

Development of Dicationic Bisguanidine-Arylfuran Derivatives as Potent Agents against Gram-Negative Bacteria.

Antibiotic resistance among bacteria is a growing global challenge. A major reason for this is the limited progress in developing new classes of antibiotics active against Gram-negative bacteria. Here, we investigate the antibacterial activity of a dicationic bisguanidine-arylfuran, originally developed as an antitrypanosomal agent, and new derivatives thereof.

Lsm7 phase-separated condensates trigger stress granule formation.

Stress granules (SGs) are non-membranous organelles facilitating stress responses and linking the pathology of age-related diseases. In a genome-wide imaging-based phenomic screen, we identify Pab1 co-localizing proteins under 2-deoxy-D-glucose (2-DG) induced stress in Saccharomyces cerevisiae. We find that deletion of one of the Pab1 co-localizing proteins, Lsm7, leads to a significant decrease in SG formation.

Post-transcriptional regulation during stress.

To remain competitive, cells exposed to stress of varying duration, rapidity of onset, and intensity, have to balance their expenditure on growth and proliferation versus stress protection. To a large degree dependent on the time scale of stress exposure, the different levels of gene expression control: transcriptional, post-transcriptional, and post-translational, will be engaged in stress responses. The post-transcriptional level is appropriate for minute-scale responses to transient stress, and for recovery upon return to normal conditions.

Global SLAM-seq for accurate mRNA decay determination and identification of NMD targets.

Gene expression analysis requires accurate measurements of global RNA degradation rates, earlier problematic with methods disruptive to cell physiology. Recently, metabolic RNA labeling emerged as an efficient and minimally invasive technique applied in mammalian cells. Here, we have adapted SH-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) for a global mRNA stability study in yeast using 4-thiouracil pulse-chase labeling.

Oxygenated Cyclohexene Derivatives from the Stem and Root Barks of .

Five new cyclohexene derivatives, dipandensin A and B ( and ) and pandensenols A-C (-), and 16 known secondary metabolites (-) were isolated from the methanol-soluble extracts of the stem and root barks of . The structures were characterized by NMR spectroscopic and mass spectrometric analyses, and that of 6-methoxyzeylenol () was further confirmed by single-crystal X-ray crystallography, which also established its absolute configuration. The isolated metabolites were evaluated for antibacterial activity against the Gram-positive bacteria and and the Gram-negative bacteria , , , , and , as well as for cytotoxicity against the MCF-7 human breast cancer cell line.

A Small Molecule Targeting Human MEK1/2 Enhances ERK and p38 Phosphorylation under Oxidative Stress or with Phenothiazines.

Small molecules are routinely used to inhibit protein kinases, but modulators capable of enhancing kinase activity are rare. We have previously shown that the small molecule INR119, designed as an inhibitor of MEK1/2, will enhance the activity of its fission yeast homologue, Wis1, under oxidative stress. To investigate the generality of these findings, we now study the effect of INR119 in human cells under similar conditions.

Violacein-Induced Chaperone System Collapse Underlies Multistage Antiplasmodial Activity.

Antimalarial drugs with novel modes of action and wide therapeutic potential are needed to pave the way for malaria eradication. Violacein is a natural compound known for its biological activity against cancer cells and several pathogens, including the malaria parasite, (Pf). Herein, using chemical genomic profiling (CGP), we found that violacein affects protein homeostasis.

Yeast-based high-throughput screens for discovery of kinase inhibitors for neglected diseases.

The discovery and development of a new drug is a complex, time consuming and costly process that typically takes over 10 years and costs around 1 billion dollars from bench to market. This scenario makes the discovery of novel drugs targeting neglected tropical diseases (NTDs), which afflict in particular people in low-income countries, prohibitive. Despite the intensive use of High-Throughput Screening (HTS) in the past decades, the speed with which new drugs come to the market has remained constant, generating doubts about the efficacy of this approach.

Antibacterial and cytotoxic biflavonoids from the root bark of Ochna kirkii.

The new isoflavonoid kirkinone A (1) and biflavonoid kirkinone B (2) along with six known compounds (3-8) were isolated from the methanolic extract of the root bark of Ochna kirkii. The compounds were identified by NMR spectroscopic and mass spectrometric analyses. Out of the eight isolated natural products, calodenin B (4) and lophirone A (6) showed significant antibacterial activity against the Gram-positive bacterium Bacillus subtilis with MIC values of 2.

Biflavanones, Chalconoids, and Flavonoid Analogues from the Stem Bark of .

Two new biflavanones ( and ), three new bichalconoids (-), and 11 known flavonoid analogues (-) were isolated from the stem bark extract (CHOH-CHCl, 7:3, v/v) of . The structures of the isolated metabolites were elucidated by NMR spectroscopic and mass spectrometric analyses. The crude extract and the isolated metabolites were evaluated for antibacterial activity against (Gram-positive) and (Gram-negative) as well as for cytotoxicity against the MCF-7 human breast cancer cell line.

A High-Throughput Method for Screening for Genes Controlling Bacterial Conjugation of Antibiotic Resistance.

The rapid horizontal transmission of antibiotic resistance genes on conjugative plasmids between bacterial host cells is a major cause of the accelerating antibiotic resistance crisis. There are currently no experimental platforms for fast and cost-efficient screening of genetic effects on antibiotic resistance transmission by conjugation, which prevents understanding and targeting conjugation. We introduce a novel experimental framework to screen for conjugation-based horizontal transmission of antibiotic resistance between >60,000 pairs of cell populations in parallel.

Antibacterial and cytotoxic prenylated dihydrochalcones from Eriosema montanum.

Two new prenylated dihydrochalcones (1,2) and eighteen known secondary metabolites (3-20) were isolated from the CHCl-MeOH (1:1) extracts of the roots, the stem bark and the leaves of Eriosema montanum Baker f. (Leguminosae). The structures of the isolated compounds were characterized by NMR, IR, and UV spectroscopic and mass spectrometric analyses.

Caffeine Stabilises Fission Yeast Wee1 in a Rad24-Dependent Manner but Attenuates Its Expression in Response to DNA Damage.

The widely consumed neuroactive compound caffeine has generated much interest due to its ability to override the DNA damage and replication checkpoints. Previously Rad3 and its homologues was thought to be the target of caffeine's inhibitory activity. Later findings indicate that the Target of Rapamycin Complex 1 (TORC1) is the preferred target of caffeine.