Biology subjects

Baum, J.

Publications and source records attributed to Baum, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Low Symbiodiniaceae diversity across Acropora hosts on the Central Pacific atoll Kiritimati

The transformative impacts of global bleaching events are now a ubiquitous feature of coral reefs, often resulting in taxonomically simplified coral assemblages that can persist long-term due to ongoing ocean warming, heatwaves, and localized anthropogenic stressors. Understanding to what extent these processes shape symbiont biodiversity continues to be a major knowledge gap. Here, we examined Acropora host and symbiont communities on Kiritimati (Republic of Kiribati), seven and a half years after the 20152016 El Nino-associated marine heatwave, which caused a near total loss of the genus in the atoll's shallow reefs. We quantified Acropora cover and growth-form composition at 37 sites spanning a gradient of local human disturbance and characterised Symbiodiniaceae communities using ITS2 DNA metabarcoding from 109 coral tissue samples at 13 of the sites. Corymbose and tabular Acropora growth forms remained evenly represented across the atoll and cover declined with increasing human disturbance. Symbiodiniaceae communities were dominated by Cladocopium with 93 % of colonies associated with a single ITS2 profile. Communities were homogenous, with low diversity and insignificant differences amongst growth forms, but slight differences across disturbance levels. DNA barcoding of the PaxC intron identified the majority of host colonies as most similar to Acropora granulosa (62 %) and Acropora hyacinthus (24 %). Although dominance by a single symbiont lineage is common among Acropora species across the Pacific, the low Symbiodiniaceae diversity observed at Kiritimati contrasts with the substantial within- and among-lineage diversity documented elsewhere. The depauperate Symbiodiniaceae communities observed in this study may thus represent a lasting legacy of the 2015-2016 disturbance, with the recovering Acropora assemblage representing an early stage of community reassembly drawing from a potentially depleted environmental symbiont pool.

ecology↗

bioRxiv2026

Expectation Shapes Neural Preparation for AI-generated and Real Image Processing: Evidence from EEG

AbstractAI-generated images, videos, and news have become an inseparable part of daily life, leading to increasing skepticism toward online information. Understanding how expectations about the presence of AI-generated content influence perception is crucial for elucidating the underlying neural mechanisms and facilitating the generation of naturalistic avatars. In this study, we analyzed an existing EEG dataset (N = 29) in which participants viewed emotional facial photographs of only real individuals while being informed that upcoming faces were either real ("REAL") or AI-generated ("FAKE"). We examined pre-stimulus oscillatory activities in the one-second EEG interval before stimulus onset and found significantly lower alpha power when participants expected "FAKE" compared to "REAL" faces. This effect was region-specific, particularly in right occipito-parietal and temporo-parietal regions, as identified by both sensor- and source- level analyses. In addition, the modulation effect between pre-stimulus alpha activity and post-stimulus event-related potentials (ERPs) was measured. A significant correlation between changes in late positive potential (LPP) amplitudes and pre-stimulus alpha power was observed exclusively for "FAKE" smiling faces, consistent with our previous findings. These results suggest that AI-related expectations modulate neural preparatory states, with lower alpha activity presumably reflecting increased attentional demands for stimuli believed to be artificially generated. This study demonstrates that top-down beliefs systematically shape both pre- and post-stimulus neural dynamics, providing new insights into how cognitive expectations bias perceptual processing, with implications for understanding human-AI interaction and improving the design and evaluation of AI- generated content in real-world contexts.

neuroscience↗

bioRxiv2026

Differential effects of α-Synuclein monomers and seeds on the material properties of Tau condensates

Tau and -Synuclein (Syn) frequently co-aggregate in various neurodegenerative disorders. Recently, Tau has been shown to form dynamic, liquid-like condensates that can recruit Syn, and potentially serve as a precursor to pathological aggregation. However, the quantitative impact of Syn on the material properties of these condensates remains elusive. Here, we measure the viscosity and interfacial tension of Tau condensates and determine how these properties are modulated by Syn monomers and fibril seeds. We find that while both forms of Syn partition efficiently into Tau condensates, they exert vastly different effects on the condensates material state. The viscosity of Tau condensates remains unchanged in the presence of Syn monomers at concentrations up to 200 {micro}M, accompanied by a moderate reduction in the condensates interfacial tension. In contrast, the addition of only 5 {micro}M Syn fibril seeds triggers rapid solidification of Tau condensates, manifested by a nearly 100-fold increase in condensate viscosity within one hour. These findings provide quantitative insights into condensate mechanics, highlighting the unique capacity of Syn seeds to drive the liquid-to-solid transition of Tau condensates that may underlie the formation of pathological aggregates.

biophysics↗

bioRxiv2026

Biomolecular condensates provide a unique environment for redox-mediated protein crosslinking

Biomolecular condensates, often formed through liquid-liquid phase separation, are dynamic cellular compartments. Here, we demonstrate that a wide range of fluorescently tagged proteins undergo inadvertent, condensate-mediated crosslinking, resulting in rapid solidification of condensates under common fluorescence imaging conditions. The process is driven by excitation-induced, short-lived reactive oxygen species (ROS), whose otherwise limited crosslinking potential becomes uniquely enabled in the dense phase. In live cells, excitation-induced ROS potently trigger stress granule formation, while the ROS-driven solidification of condensates is modulated by compartment-dependent antioxidant buffering. Our findings demonstrate that condensates create a distinct environment that enables ROS chemistry unlikely to occur in the bulk cytosol. Furthermore, the cellular redox level can be a general regulator of condensate rheology. Beyond biological insights, our findings underscore the need for scrutiny when examining fluorophore-labeled condensates.

biophysics↗

bioRxiv2026

Comparing the transmission blocking efficacy of Primaquine and Tafenoquine with in vivo pre-clinical models

The 8-aminoquinoline family are a well-established class of antimalarial drugs containing two clinically relevant analogues, primaquine and tafenoquine. These compounds have two therapeutically significant activities across the plasmodial lifecycle; elimination of Plasmodium vivax hypnozoites as part of a radical cure (relapse prevention), and as prophylactic transmission blocking compounds. Primaquine is currently recommended as a single low (0.25 mg/kg) dose administered with artemisinin-based combination therapy to reduce malarial transmission in areas at high risk of artemisinin partial resistance. Tafenoquine was approved in 2018 for radical cure when co-administered with chloroquine however, its transmission blocking efficacy in humans has not yet been fully evaluated, and direct head-to-head comparisons of transmission-blocking efficacy of primaquine and tafenoquine have not been performed. Given that primaquine and tafenoquine are presumed to have similar mechanisms of action, tafenoquine may have potential use as a transmission blocking intervention. Furthermore, tafenoquine has a substantially longer half-life than primaquine, which could provide a pharmacokinetic advantage if such efficacy is confirmed. However, assessment of 8-aminoquinoline efficacy against the sexual stages of Plasmodium is complicated by the requirement for metabolic activation to generate parasite-reactive species, limiting the utility of in vitro assays. Here, we directly compare the transmission blocking effects of primaquine and tafenoquine using two in vivo preclinical models. We titrate the transmission blocking efficacy of each compound, and evaluate the pharmacokinetics of each compound over time, linking drug exposure to efficacy. The evidence presented here suggests that beyond 24 hours, a single dose of tafenoquine is likely to have more clinically desirable pharmacokinetics, resulting in higher transmission blocking efficacy than primaquine. These findings are observed across multiple models, both in the absence or presence of a partner schizonticide and thus demonstrate a potential advantage of the utilisation of tafenoquine when compared to primaquine.

microbiology↗

bioRxiv2025

Is synuclein aggregation a derived or ancestral trait? Ancestral sequence reconstruction uncovers stepwise evolution of synuclein aggregation

Protein aggregation drives many neurodegenerative diseases, including Parkinsons disease, where misfolded -synuclein (Syn) forms fibrillar assemblies that accumulate as Lewy bodies. Although Syn aggregation has been extensively characterized, its evolutionary origins and sequence determinants remain unresolved. Here, we use ancestral sequence reconstruction (ASR) to trace the emergence of fibril-forming ability in the synuclein family. We inferred synuclein phylogeny and experimentally resurrected common ancestors, including ROOT synuclein, the last common ancestor of all synucleins, and key intermediates along the Syn lineage. Strikingly, ROOT synuclein is non-aggregating, demonstrating that fibril formation is an evolved, rather than ancestral property. Aggregation first emerges at the ancestral {beta} node, is retained in Syn, and suppressed in {beta}-synuclein. Biophysical analyses including mass spectrometry and NMR reveal that aggregation aligns with greater complexity and heterogeneity in the monomer conformational ensemble, suggesting that evolutionary sequence changes progressively remodel monomer landscapes to favor fibril formation. Complementing these insights, comparative sequence analysis reveals that the transition from ROOT to -WT is marked by the stepwise acquisition of residues critical for stabilizing the fibril core. Early mutations stabilized the {beta}-arch core, enabling the onset of fibril formation, followed by substitutions that reinforce protofilament-protofilament interactions. Together, ASR defines an evolutionary framework for synuclein aggregation linking progressive sequence evolution and conformational complexity to the molecular origins of Syn fibril formation.

biophysics↗

bioRxiv2025

Nanoscale Structural and Functional Impacts of Disease-Associated Collagen Mutations

Collagen is the most abundant structural protein in the human body, and its supramolecular organization is central to tissue mechanics and cell-matrix interactions. Integrins, key mediators of these interactions, are essential for important biological processes including adhesion, migration, differentiation, and platelet aggregation. While mutations in collagen are known to cause connective tissue disorders such as Osteogenesis Imperfecta (OI) with phenotypes ranging from mild to perinatal lethal, how these mutations alter fibril level architecture, dynamics, integrin-mediated interactions and their functional consequences at both the protein and cellular level remains poorly understood. Here, we investigated the impact of OI mutations on direct collagen-integrin interactions and on cellular responses to mutant collagen. We generated collagen-rich extra-cellular matrix (ECM) from primary dermal fibroblasts of a healthy donor (WT) and from two OI patients carrying distinct glycine mutations: G610C, associated with moderate disease, and G907D, linked to perinatal lethality. Comparative biophysical studies reveal that both mutants retain the canonical D-banding of collagen I fibrils but differ markedly at the nanoscale. G907D fibrils exhibit greater local structural perturbations and increased molecular mobility relative to the non-lethal G610C. Importantly, while cell surface adhesion and proliferation do not differ between the OI mutants, integrin binding diverges between mutants: G610C displays reduced affinity, whereas G907D exhibits enhanced affinity compared to WT. Together, these findings establish a mechanistic link between single-residue mutations, nanoscale fibril architecture and collagen-receptor interactions, and highlight how genetic or acquired collagen defects can drive ECM dysregulation.

biophysics↗

bioRxiv2024

Synergistic Multi-Pronged Interactions Mediate the Effective Inhibition of Alpha-Synuclein Aggregation by the Chaperone HtrA1

The misfolding, aggregation, and the seeded spread of alpha synuclein (-Syn) aggregates are linked to the pathogenesis of various neurodegenerative diseases, including Parkinsons disease (PD). Understanding the mechanisms by which chaperone proteins prevent the production and seeding of -Syn aggregates is crucial for developing effective therapeutic leads for tackling neurodegenerative diseases. We show that a catalytically inactive variant of the chaperone HtrA1 (HtrA1*) effectively inhibits both -Syn monomer aggregation and templated fibril seeding, and demonstrate that this inhibition is mediated by synergistic interactions between its PDZ and Protease domains and -Syn. Using biomolecular NMR, AFM and Rosetta-based computational analyses, we propose that the PDZ domain interacts with the C-terminal end of the monomer and the intrinsically disordered C-terminal domain of the -Syn fibril. Furthermore, in agreement with sequence specificity calculations, the Protease domain cleaves in the aggregation-prone NAC domain at site T92/A93 in the monomer. Thus, through multi-pronged interactions and multi-site recognition of -Syn, HtrA1* can effectively intervene at different stages along the -Syn aggregation pathway, making it a robust inhibitor of -Syn aggregation and templated seeding. Our studies illustrate, at high resolution, the crucial role of HtrA1 interactions with both the intrinsically disordered -Syn monomers and with the dynamic flanking regions around the fibril core for inhibition of aggregation. This inhibition mechanism of the HtrA1 chaperone may provide a natural mechanistic blueprint for highly effective therapeutic agents against protein aggregation. Significance StatementPD and other synucleinopathies are marked by misfolding and aggregation of -Syn, forming higher-order species that propagate aggregation in a prion-like manner. Understanding how chaperone proteins inhibit -Syn aggregation and spread is essential for therapeutic development against neurodegeneration. Through an integrative approach of solution-based NMR, AFM, aggregation kinetics, and computational analysis, we reveal how a catalytically inactive variant of the chaperone HtrA1 effectively disrupts aggregation pathways. We find that the inactive Protease and PDZ domains of HtrA1 synergistically bind to key intrinsically disordered sites on both -Syn monomers and fibrils, thereby effectively inhibiting both aggregation and templated seeding. Our work provides a natural and unique blueprint for designing inhibitors to prevent the formation and seeding of aggregates in neurodegenerative diseases.

biophysics↗

bioRxiv2024

Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease

Alpha-synuclein (Syn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinsons disease and forms intraneuronal inclusions called Lewy Bodies. While the mechanism underlying the dysregulation of Syn in Parkinsons disease is unclear, it is thought that prionoid cell-to-cell propagation of Syn has an important role. Through a high throughput screen, we recently identified 38 genes whose knock down modulates Syn propagation. Follow up experiments were undertaken for two of those genes, TAX1BP1 and ADAMTS19, to study the mechanism with which they regulate Syn homeostasis. We used a recently developed M17D neuroblastoma cell line expressing triple mutant (E35K+E46K+E61K) "3K" Syn under doxycycline induction. 3K Syn spontaneously forms inclusions that show ultrastructural similarities to Lewy Bodies. Experiments using that cell line showed that TAX1BP1 and ADAMTS19 regulate how Syn interacts with lipids and phase separates into inclusions, respectively, adding to the growing body of evidence implicating those processes in Parkinsons disease. Through RNA sequencing, we identified several genes that are differentially expressed after knock-down of TAX1BP1 or ADAMTS19. Burden analysis revealed that those differentially expressed genes (DEGs) carry an increased frequency of rare risk variants in Parkinsons disease patients versus healthy controls, an effect that was independently replicated across two separate cohorts (GP2 and AMP-PD). Weighted gene co-expression network analysis (WGCNA) showed that the DEGs cluster within modules in regions of the brain that develop high degrees of Syn pathology (basal ganglia, cortex). We propose a novel model for the genetic architecture of sporadic Parkinsons disease: increased burden of risk variants across genetic networks dysregulates pathways underlying Syn homeostasis, thereby leading to pathology and neurodegeneration.

cell biology↗

bioRxiv2024

Direct quantification of condensate material properties in live cells reveals the regulation of synapsin condensates viscoelasticity by alpha-synuclein

Synapsin and -synuclein represent a growing list of condensate-forming proteins where the material states of condensates are directly linked to cellular functions (e.g., neurotransmission) and pathology (e.g., neurodegeneration). However, quantifying condensate material properties in living systems has been a significant challenge. To address this, we develop MAPAC (micropipette aspiration and whole-cell patch clamp), a platform that allows direct material quantification of condensates in live cells. We find 10,000-fold variations in the viscoelasticity of synapsin condensates, regulated by the partitioning of -synuclein, a marker for synucleinopathies. Through in vitro reconstitutions, we identify 4 molecular factors that distinctly regulate the viscosity and interfacial tension of synapsin condensates, verifying the cellular effects of -synuclein. Overall, our study provides unprecedented quantitative insights into the material properties of neuronal condensates and reveals a crucial role of -synuclein in regulating condensate viscoelasticity. Furthermore, we envision MAPAC applicable to study a broad range of condensates in vivo.

cell biology↗

bioRxiv2023

A novel computational pipeline for var gene expression augments the discovery of changes in the Plasmodium falciparum transcriptome during transition from in vivo to short-term in vitro culture

The pathogenesis of severe Plasmodium falciparum malaria involves cytoadhesive microvascular sequestration of infected erythrocytes, mediated by P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 variants are encoded by the highly polymorphic family of var genes, the sequences of which are largely unknown in clinical samples. Previously, we published new approaches for var gene profiling and classification of predicted binding phenotypes in clinical P. falciparum isolates (Wichers et al., 2021), which represented a major technical advance. Building on this, we report here a novel method for var gene assembly and multidimensional quantification from RNA-sequencing that outperforms the earlier approach of Wichers et al., 2021 on both laboratory and clinical isolates across a combination of metrics. Importantly, the tool can interrogate the var transcriptome in context with the rest of the transcriptome and can be applied to enhance our understanding of the role of var genes in malaria pathogenesis. We applied this new method to investigate changes in var gene expression through early transition of parasite isolates to in vitro culture, using paired sets of ex vivo samples from our previous study, cultured for up to three generations. In parallel, changes in non-polymorphic core gene expression were investigated. Modest but unpredictable var gene switching and convergence towards var2csa were observed in culture, along with differential expression of 19% of the core transcriptome between paired ex vivo and generation 1 samples. Our results cast doubt on the validity of the common practice of using short-term cultured parasites to make inferences about in vivo phenotype and behaviour.

bioinformatics↗

bioRxiv2022

A fast-killing tyrosine amide ((S)-SW228703) with blood and liver-stage antimalarial activity associated with the Cyclic Amine Resistance Locus (PfCARL)

Current malaria treatments are threatened by drug resistance and new drugs are urgently needed. In a phenotypic screen for new antimalarials, we identified (S)-SW228703 ((S)-SW703), a tyrosine amide with asexual blood and liver stage activity and a fast-killing profile. Resistance to (S)-SW703 is associated with mutations in Plasmodium falciparum cyclic amine resistance locus (PfCARL) and P. falciparum acetyl CoA transporter (PfACT), similarly to several other compounds that share features such as fast activity and liver-stage activity. Compounds with these resistance mechanisms are thought to act in the ER, though their target(s) are unknown. The tyramine of (S)-SW703 is shared with some reported PfCARL-associated compounds; however, we observed that strict S-stereochemistry was required for activity of (S)-SW703, suggesting differences in mechanism of action or binding mode. (S)-SW703 provides a new chemical series with broad activity on multiple life-cycle stages and a fast-killing mechanism of action, available for lead optimization to generate new treatments for malaria.

microbiology↗

bioRxiv2022

Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design

Malaria is responsible for more than a half million deaths per year. The Plasmodium parasites responsible continue to develop resistance to all known agents, despite treatment with different antimalarial combinations. The atypical Myosin A motor (PfMyoA) is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays, X-ray crystallography and molecular dynamics, we demonstrate that KNX-002 targets a novel pocket in PfMyoA, sequestering it in a post-rigor state detached from actin. KNX-002 binding affects Mg2+ coordination near ATP, preventing ATP hydrolysis and thus inhibiting motor activity. This first-in-class small-molecule inhibitor of PfMyoA paves the way for developing a new generation of antimalarial treatments.

molecular biology↗

bioRxiv2022

Electricity-free nucleic acid extraction method from dried blood spots on filter paper for point-of-care diagnostics

BackgroundNucleic acid extraction is a crucial step for molecular biology applications, being a determinant for any diagnostic test procedure. Dried blood spots (DBS) have been used for decades for serology, drug monitoring, environmental investigations, and molecular studies. Nevertheless, nucleic acid extraction from DBS remains one of the main challenges to translate them to the point-of-care (POC). MethodWe have developed a fast nucleic acid extraction (NAE) method from DBS which is electricity-free and relies on cellulose filter papers (DBSFP). The performance of NAE was assessed with loop-mediated isothermal amplification (LAMP), targeting the human reference gene beta-actin. The developed method was evaluated against FTA cards and magnetic bead-based purification, using time-to-positive (min) for comparative analysis. We optimised and validated the developed method for elution (eluted disk) and disk directly in the reaction (in-situ disk), RNA and DNA detection, and whole blood stored in anticoagulants (K2EDTA and lithium heparin). Furthermore, the compatibility of DBSFP with colourimetric detection was studied to show the transferability to the POC. ResultsThe proposed DBSFP is based on grade 3 filter paper pre-treated with 8% (v/v) igepal surfactant, 1 min washing step with PBS 1X and elution in TE 1X buffer after 5 min incubation at room temperature, enabling NAE under 7 min. Obtained results were comparable to gold standard methods across tested matrices, targets and experimental conditions, demonstrating the versatility of the methodology. Lastly, eluted disk colourimetric detection was achieved with a sample-to-result turnaround time under 35 min. ConclusionsThe developed method is a fast, electricity-free, and low-cost solution for NAE from DBSFP enabling molecular testing in virtually any POC setting.

molecular biology↗

bioRxiv2021

4D live-cell imaging of microgametogenesis in the human malaria parasite Plasmodium falciparum

Formation of gametes in the malaria parasite occurs in the midgut of the mosquito and is critical to onward parasite transmission. Transformation of the male gametocyte into microgametes, called microgametogenesis, is an explosive cellular event and one of the fastest eukaryotic DNA replication events known. The transformation of one microgametocyte into eight flagellated microgametes requires reorganisation of the parasite cytoskeleton, replication of the 22.9 Mb genome, axoneme formation and host erythrocyte egress, all of which occur simultaneously in <20 minutes. Whilst high-resolution imaging has been a powerful tool for defining stages of microgametogenesis, it has largely been limited to fixed parasite samples, given the speed of the process and parasite photosensitivity. Here, we have developed a live-cell fluorescence imaging workflow that captures the explosive dynamics of microgametogenesis in full. Using the most virulent human malaria parasite, Plasmodium falciparum, our live-cell approach combines three-dimensional imaging through time (4D imaging) and covers early microgametocyte development through to microgamete release. Combining live-cell stains for DNA, tubulin and the host erythrocyte membrane, 4D imaging enables definition of the positioning of newly replicated and segregated DNA. It also shows the microtubular cytoskeleton, location of newly formed basal bodies and elongation of axonemes, as well as behaviour of the erythrocyte membrane, including its specific perforation prior to microgamete egress. 4D imaging was additionally undertaken in the presence of known transmission-blocking inhibitors and the untested proteasomal inhibitor bortezomib. Here, for the first time we find that bortezomib inhibition results in a clear block of DNA replication, full axoneme nucleation and elongation. These data not only define a framework for understanding microgametogenesis in general but also suggest that the process is critically dependent on proteasomal activity, helping to identify potentially novel targets for transmission-blocking antimalarial drug development.

microbiology↗

bioRxiv2021

Plasmodium falciparum protein Pfs16 is a target for transmission-blocking antimalarial drug development

Phenotypic cell-based screens are critical to the discovery of new antimalarial lead compounds. However, identification and validation of cellular targets of lead compounds is required following discovery in a phenotypic screen. We recently discovered a Plasmodium transmission-blocking N-((4-hydroxychroman-4-yl)methyl)-sulfonamide (N-4HCS) compound, DDD01035881, in a phenotypic screen. DDD01035881 and its potent derivatives have been shown to block Plasmodium male gamete formation (microgametogenesis) with nanomolar activity. Here, we synthesised a photoactivatable N-4HCS derivative, probe 2, to identify the N-4HCS cellular target. Using probe 2 in photo-affinity labelling coupled with mass spectrometry, we identified the 16 kDa Plasmodium falciparum parasitophorous vacuole membrane protein Pfs16 as the likely cellular target of the N-4HCS series. Further validating Pfs16 as the cellular target of the N-4HCS series, the Cellular Thermal Shift Assay (CETSA) confirmed DDD01035881 stabilised Pfs16 in lysate from activated mature gametocytes. Additionally, photo-affinity labelling combined with in-gel fluorescence and immunoblot analysis confirmed the N-4HCS series interacted with Pfs16. High-resolution, widefield fluorescence and electron microscopy of N-4HCS-inhibited parasites was found to result in a cell morphology entirely consistent with targeted gene disruption of Pfs16. Taken together, these data strongly implicate Pfs16 as the target of DDD01035881 and establish the N-4HCS scaffold family as a powerful starting point from which future transmission-blocking antimalarials can be developed.

microbiology↗

bioRxiv2021

Tannic Acid Inhibits α-Synuclein Amyloid Fibril Formation via Binding to the Monomer N-terminal Domain

-Synuclein (S) is an intrinsically disordered protein (IDP) that aggregates into amyloid fibrils during the progression of Parkinsons Disease and other synucleinopathies. The N-terminal domain (residues 1-60) is now understood to play a critical role in the initial nucleation of aggregation, as well as a pivotal role in the monomer-fibril interaction underlying amyloid seeding. Here we report on the interaction between S and the polyphenol tannic acid (TA), where a combination of solution NMR, atomic force microscopy (AFM), and ThT assays have identified that TA targets the S N-terminal domain to inhibit amyloid fibril formation in a pH dependent manner. This work highlights the importance of targeting the N-terminus of S to arrest fibril formation, and suggests the importance of including polyphenolic moieties in future amyloid inhibitors.

biochemistry↗

bioRxiv2021

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (ACS) inhibitor to enter preclinical development. Our studies demonstrated attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound showed exceptional in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocked P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identified ACS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. MMV693183 was well adsorbed after oral administration in mice, rats and dogs. Pharmacokinetic - pharmacodynamic modelling predicted that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. In conclusion, the ACS-targeting compound MMV693183 represents a promising addition to the portfolio of antimalarials in (pre)clinical development with a novel mode of action for the treatment of malaria and blocking transmission.

microbiology↗