Biology subjects

Agrawal, R.

Publications and source records attributed to Agrawal, R..

At least 19 recordsLinked to original sources

bioRxiv2026

Mechanistical and structural basis of Kv channel inhibition by 4 aminopyridine

Inhibition of Kv channels by 4-aminopyridine (4AP) improves motor function in multiple sclerosis by enhancing neuronal excitability. The mechanism of inhibition and the structural basis of 4AP binding to Kv channels remain unclear. Here, we determined the structure of the Shaker V369I-I372L-S376T (ILT) mutant bound to 4AP at 3.3 [A], demonstrating that 4AP binds to the closed state of the channel. This structure is inconsistent with an open channel block mechanism. Electrophysiology experiments show that 4AP binds even when intracellular pore access is constitutively blocked, suggesting that 4AP enters the pore through membrane-facing fenestrations. MD simulations and mutational analysis agree with the proposed fenestration pathway and suggest that 4AP binds in its neutral form. These results support a mechanism where 4AP binds to a partially activated closed state that prevents complete activation of Kv channels, explaining its pharmacological activity.

biophysics↗

bioRxiv2026

3D chromatin compartment of round spermatids encodes the spatiotemporal program of histone-to-protamine exchange in spermiogenesis

Sperm formation requires a radical chromatin reorganization, where nucleosomes are replaced by transition proteins (TNPs) and subsequently by protamines (PRM1 and PRM2). Although essential for fertility, the regulatory logic governing this exchange is unknown, but its presumed to be stochastic and unregulated. Using endogenously tagged PRM mouse models and stage-resolved, genome-wide profiling, we revise the order of histone-to-protamine exchange and show that the chromatin remodeling process is highly programmed. Imaging and biochemical experiments reveal a direct histone-to-PRM1 exchange, while TNPs appear after PRM1 but precede PRM2 incorporation. This temporal uncoupling of PRM1 and PRM2 incorporation coincides with dynamic, region-specific chromatin remodeling that is not governed by histone acetylation but is instructed by the three-dimensional nuclear architecture of round spermatids. Therefore, by integrating ATAC-seq, CUT&Tag, and Hi-C, we define a compartment-encoded "blueprint" that prescribes the assembly of the mature sperm epigenome and establishes a complex molecular hierarchy for the histone-to-protamine exchange.

genomics↗

bioRxiv2025

A hidden protamine PTM code in sperm generates heterogeneous chromatin states and finetunes reproductive fitness

Traditionally, the sperm genome is thought to be packaged by protamines into a uniformly compact and inert chromatin structure. Here, we challenge this long-standing view by demonstrating that protamine post-translational modifications (PTMs) present on distinct protamine molecules create discrete protamine-DNA chromatin states, ranging from weak to tightly associated chromatin configurations. Loss of these modifications alters protamine-DNA interactions in vitro and in vivo, compromising sperm chromatin integrity and impairing fertility. Therefore, these findings demonstrate that protamines do not merely serve as inert packaging proteins; rather protamine PTMs establish functional heterogeneity within sperm chromatin, creating compartment-like domains analogous to those in somatic cells. Thus, PTMs allow protamines to do more than simply compact the paternal genome--they likely encode a molecular blueprint that orchestrates the timely unpacking and reorganization of the paternal genome after fertilization.

molecular biology↗

bioRxiv2025

The Closed State of the Shaker Potassium Channel and the Mechanism of Voltage Activation

To understand the process of voltage activation in Kv channels, we determined the cryo-EM structure of the Shaker channel ILT mutant (V369I, I372L, S376T), known to partially decouple the gating charge movement of the voltage sensing domain (VSD) and the opening of the pore domain (PD). The structure captures a previously unobserved intermediate state in which the VSD is only partially activated while the PD remains closed. Combined with computational modeling based on AlphaFold2 predictions and molecular dynamics simulations, it is shown that VSD activation does not mechanically pull the gate open, but instead induces a dynamic shift in the population equilibrium of the VSD-PD linker, providing the basis for electromechanical coupling between the two domains.

biophysics↗

bioRxiv2025

GPR17 modulates oligodendrocyte precursor cell maturation during development but has limited impact on myelin regeneration following demyelinating insults

Pharmacological enhancement of myelin regeneration is broadly recognized as the next frontier in therapeutic approaches for demyelinating diseases of the CNS such as multiple sclerosis. However, although several molecular targets for remyelination have been tested preclinically and in clinical trials, an efficacious and safe myelin repair treatment is yet to be developed. One promising molecular target to enhance myelin repair is the G protein-coupled receptor (GPCR) GPR17, which has been proposed to play a central role in the transition from early oligodendrocyte progenitor cells (OPC) into pre-myelinating oligodendrocytes. These findings are largely supported by studies using transgenic mice where GPR17 deletion results in developmental hypermyelination. Additionally, pharmacological modulation of GPR17 activity has been reported to enhance oligodendrocyte precursor cell (OPC) maturation and myelination. In our studies aimed to characterize and pharmacologically validate GPR17 as a viable target for drug development, we established by means of transcriptional profiling of GPR17 knockout versus wild type OPCs, that absence of this GPCR results in a gene signature revealing minor changes in myelin protein gene expression. Furthermore, blocking GPR17 receptor activity in OPC cultures using selective and potent antagonists or inverse agonists, results in limited enhancement of maturation and myelination in vitro. Importantly, remyelination in both the cuprizone and lysolecithin-induced demyelination models was not enhanced in the absence of GPR17. Our data demonstrate that GPR17 plays a minor role in OPC differentiation during development, and pharmacological modulation of its activity has a marginal effect on oligodendrocyte precursor maturation and myelin regeneration after injury.

neuroscience↗

bioRxiv2025

Decoding Breast Cancer Heterogeneity via Multi-Omics Integration and Language Model-Based Interpretation

We present a novel pipeline combining Multi-Omics Factor Analysis (MOFA) and fine-tuned Large Language Models (LLMs) to predict breast cancer subtypes using proteomics, DNA methylation, and RNA-Seq data. Breast cancer is a heterogeneous disease characterized by diverse molecular alterations across multiple biological layers, necessitating integrative approaches for accurate subtype classification. Our methodology leverages MOFA for dimensionality reduction to identify key latent factors driving het-erogeneity, followed by LLM fine-tuning on these multi-omics signatures to enhance prediction accuracy. MOFA analysis identified five key latent factors capturing distinct biological processes: immune response, cell cycle regulation, metabolic reprogramming, tumor microenvironment interactions, and DNA repair mechanisms. We extracted the top features per omics layer for each factor and performed Gene Set Enrichment Analysis (GSEA) to characterize their biological significance. Our LLM, trained on curated multi-omics signatures and clinical metadata encoded as structured text prompts, significantly outperformed conventional statistical models in subtype classification, achieving AUC=0.93 and accuracy=0.89, compared to Random Forest (AUC=0.87, accuracy=0.82) and SVM (AUC=0.85, accuracy=0.80). The superior performance of our approach is attributed to the LLMs ability to capture complex, non-linear relationships and hierarchical feature interactions across omics layers. This integrative pipeline provides both improved predictive performance and interpretable biological insights, offering potential for enhanced clinical decision-making in breast cancer management.

cancer biology↗

bioRxiv2025

Impairment in axonal translation and cytoplasmic viscosity during aging in sensory neurons

Mitochondria are trafficked along axons and provide the energy required for several intracellular mechanisms including molecular transport and local translation, which is believed to contribute to the homeostasis of the axonal compartment. Decline in mitochondria activity is one of the hallmarks of aging. It is still unclear, though, whether this decline corresponds to a concomitant reduction in the extent of axonal translation during aging. Using live cell imaging of sensory neurons, we found a significant decrease in the number of active mitochondria and the percentage of mitochondria localized to axons in aged mice compared to young mice. This decrease was mirrored by a loss of intracellular ATP as well as an ATP-dependent decrease in axoplasmic viscosity. In addition, the size of G3BP1 positive axonal granules and the number of FMRP axonal granules increased. Cumulatively, we found a functional decrease in the overall level of axonal translation in aged neurons. We were able to rescue this effect by increasing ATP synthesis, which induced a global decrease in axoplasmic viscosity, while promoting RNA granule solubilization and boosting axonal translation. Proteomic analysis of newly synthesized proteins in axons of aged vs young neurons revealed a dysregulation of pathways related to axonal biology and growth. We identified MAP1B and STAT3 as proteins whose axonal local synthesis was impaired in aged axons, and more notably show that this impairment could be rescued by increasing ATP synthesis. We believe that this research sheds light on axonal translation in aged neurons and its relationship with energy sources inside the axonal compartment, possibly presenting an opportunity for future therapeutics.

neuroscience↗

bioRxiv2025

OGDHL regulates nucleotide metabolism, tumor growth, and neuroendocrine marker expression in prostate cancer

As cancer cells evade therapeutic pressure and adopt alternate lineage identities not commonly observed in the tissue of origin, they likely adopt alternate metabolic programs to support their evolving demands. Targeting these alternative metabolic programs in distinct molecular subtypes of aggressive prostate cancer may lead to new therapeutic approaches to combat treatment-resistance. We identify the poorly studied metabolic enzyme Oxoglutarate Dehydrogenase-Like (OGDHL), named for its structural similarity to the tricarboxylic acid (TCA) cycle enzyme Oxoglutarate Dehydrogenase (OGDH), as an unexpected regulator of tumor growth, treatment-induced lineage plasticity, and DNA Damage in prostate cancer. While OGDHL has been described as a tumor-suppressor in various cancers, we find that its loss impairs prostate cancer cell proliferation and tumor formation. Loss of OGDHL profoundly alters Androgen Receptor inhibition-induced plasticity, including suppressing the neuroendocrine markers DLL3 and HES6, induces accumulation of the DNA damage response marker {gamma}H2AX, and reduces nucleotide synthesis. Our data suggest that OGDHL has minimal impact on TCA cycle activity, and that mitochondrial localization is not required for its regulation of prostate cancer plasticity and nucleotide metabolism. Finally, we demonstrate that OGDHL expression is tightly correlated with neuroendocrine differentiation in clinical prostate cancer. These findings underscore the importance of investigating poorly characterized metabolic genes as potential regulators of distinct molecular subtypes of aggressive cancer.

cancer biology↗

bioRxiv2025

Scaled multidimensional assays of variant effect identify sequence-function relationships in hypertrophic cardiomyopathy

BackgroundAn estimated 1 in 500 people live with hypertrophic cardiomyopathy (HCM), a disease for which genetic diagnosis can identify family members at risk, and increasingly guide therapy. Mutations in the myosin binding protein C3 (MYBPC3) gene account for a significant proportion of HCM cases. However, many of these variants are classified as variants of uncertain significance (VUS), complicating clinical decision-making. Scalable methods for variant interpretation in disease-specific cell types are crucial for understanding variant impact and uncovering disease mechanisms. MethodsWe developed a scaled multidimensional mapping strategy to evaluate the functional impact of variants across a critical domain of MYBPC3. We incorporate saturation base editing at the native MYBPC3 locus, a long-read RNA sequencing-enabled assay of variant splice effects, and measurements of HCM-relevant phenotypes, including MYBPC3 abundance, hypertrophic signaling, and ubiquitin-proteasome function in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). ResultsOur multidimensional mapping strategy enabled high-resolution functional analysis of MYBPC3 variants in iPSC-CMs. Targeted transient base editing generated a comprehensive variant library at the native locus, capturing diverse variant effects on cellular HCM-relevant phenotypes. Our massively parallel splicing assay identified novel splice-disrupting variants. Integration of functional assays revealed that decreased MYBPC3 abundance is a key driver of HCM-related phenotypes. In parallel, downregulation of protein degradation was observed as a compensatory response to MYBPC3 loss of function, and novel disease mechanisms were identified for missense variants near a critical binding domain, underscoring their contribution to pathogenesis. Bayesian estimates of variant effects enable the reclassification of clinical variants. ConclusionsThis work provides a platform for extending genome engineering in iPSCs to multiplexed assays of variant effects across diverse disease-relevant cellular phenotypes, enhancing the understanding of variant pathogenicity and uncovering novel biological mechanisms that could inform therapeutic strategies.

genetics↗

bioRxiv2025

Human plastins are novel cytoskeletal pH sensors with a reduced F-actin bundling capacity at basic pH

Intracellular pH (pHi) is a fundamental component of cell homeostasis. Controlled elevations in pHi precede and accompany cell polarization, cytokinesis, and directional migration. pH dysregulation contributes to cancer, neurodegenerative diseases, diabetes, and other metabolic disorders. While cytoskeletal rearrangements are crucial for these processes, only a few cytoskeletal proteins, namely Cdc42, cofilin, talin, cortactin, -actinin, and AIP1 have been documented as pH sensors. Here, we report that actin-bundling proteins plastin 2 (PLS2, aka LCP1) and plastin 3 (PLS3) respond to physiological scale pH fluctuations by a reduced F-actin bundling at alkaline pH. The inhibition of PLS2 actin-bundling activity at elevated pH stems from the reduced affinity of the N-terminal actin-binding domain (ABD1) to actin. In fibroblast cells, elevated cytosolic pH caused the dissociation of ectopically expressed PLS2 from actin structures, whereas acidic conditions promoted its tighter association with focal adhesions and stress fibers. We identified His207 as one of the pH-sensing residues whose mutation to Lys and Tyr reduces pH sensitivity by enhancing and inhibiting the bundling ability, respectively. Our results suggest that weaker actin bundling by plastin isoforms at alkaline pH favors higher dynamics of the actin cytoskeleton. Therefore, like other cytoskeleton pH sensors, plastins promote disassembly and faster dynamics of cytoskeletal components during cytokinesis and cell migration. Since both plastins are implemented in cancer, their pH sensitivity may contribute to the accelerated proliferation and enhanced invasive and metastatic potentials of cancer cells at alkaline pHi. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/645573v1_ufig1.gif" ALT="Figure 1"> View larger version (69K): org.highwire.dtl.DTLVardef@18430a4org.highwire.dtl.DTLVardef@19584b1org.highwire.dtl.DTLVardef@13a8354org.highwire.dtl.DTLVardef@840dc3_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

The Landscape of Prostate Tumour Methylation

Prostate cancer is characterized by profound clinical and molecular heterogeneity. While its genomic heterogeneity is well-characterized, its epigenomic heterogeneity remains less understood. We therefore created a compendium of 3,001 multi-ancestry prostate methylomes spanning normal tissue through localized disease of all grades to poly-metastatic disease. A subset of 884 samples had multi-omic DNA and/or RNA characterization. We identify four epigenomic subtypes that risk-stratify patients and reflect distinct evolutionary trajectories. We demonstrate extensive regulatory interplay between DNA copy number and methylation, with transcriptional consequences that vary across genes and disease stages. We define epigenetic dysregulation signatures for 15 important clinico-molecular features, creating predictive models for each. For example, we identify specific epigenetic features that predict patient outcome and are synergistic with clinical prognostic features. These results define a complex interplay between tumour genetics and epigenetics that converges to modify gene-expression programs and clinical presentation, in part through modulation of epigenetic aging.

cancer biology↗

bioRxiv2024

Hydrogen sulfide (H2S) coordinates redox balance, carbon metabolism, and mitochondrial bioenergetics to suppress SARS-CoV-2 infection.

Viruses exploit host metabolism for replication and immune-regulation. Understanding how SARS-CoV-2 alters the host metabolism may lead to treatments for COVID-19. We report that a ubiquitous gaseous molecule, hydrogen sulfide (H2S), regulates redox, metabolism, and mitochondrial bioenergetics to control SARS-CoV-2. Virus replication is associated with down-regulation of the H2S-producing enzymes cystathionine-{beta}-synthase (CBS), cystathionine-{gamma}-lyase (CTH), and 3-mercaptopyruvate sulfurtransferase (3-MST), resulting in diminished endogenous H2S levels. Inhibition of CTH resulted in SARS-CoV-2 proliferation. A slow-releasing H2S donor, GYY4137, diminished virus replication by inducing Nrf2/Keap1 pathway, restoring redox balance and mitochondrial bioenergetics. Treatment of SARS-CoV-2-infected animals with GYY4137 suppressed viral replication, ameliorated respiratory pathology, and restored antioxidant gene expression. Notably, whole-body plethysmography showed improved pulmonary function variables, including pulmonary obstruction and end-expiratory pause upon GYY4137 treatment in vivo. Data extend our understanding of H2S-mediated regulation of viral-infections, and open new avenues for investigating the pathogenic mechanisms and therapeutic opportunities for coronavirus-associated disorders.

microbiology↗

bioRxiv2024

StableLift: Optimized Germline and Somatic Variant Detection Across Genome Builds

Reference genomes are foundational to modern genomics. Our growing understanding of genome structure leads to continual improvements in reference genomes and new genome "builds" with incompatible coordinate systems. We quantified the impact of genome build on germline and somatic variant calling by analyzing tumour-normal whole-genome pairs against the two most widely used human genome builds. The average individual had a build-discordance of 3.8% for germline SNPs, 8.6% for germline SVs, 25.9% for somatic SNVs and 49.6% for somatic SVs. Build-discordant variants are not simply false-positives: 47% were verified by targeted resequencing. Build-discordant variants were associated with specific genomic and technical features in variant- and algorithm-specific patterns. We leveraged these patterns to create StableLift, an algorithm that predicts cross-build stability with AUROCs of 0.934 {+/-} 0.029. These results call for significant caution in cross-build analyses and for use of StableLift as a computationally efficient solution to mitigate inter-build artifacts.

genomics↗

bioRxiv2024

Ultrack: pushing the limits of cell tracking across biological scales

Tracking live cells across 2D, 3D, and multi-channel time-lapse recordings is crucial for understanding tissue-scale biological processes. Despite advancements in imaging technology, achieving accurate cell tracking remains challenging, particularly in complex and crowded tissues where cell segmentation is often ambiguous. We present Ultrack, a versatile and scalable cell-tracking method that tackles this challenge by considering candidate segmentations derived from multiple algorithms and parameter sets. Ultrack employs temporal consistency to select optimal segments, ensuring robust performance even under segmentation uncertainty. We validate our method on diverse datasets, including terabyte-scale developmental time-lapses of zebrafish, fruit fly, and nematode embryos, as well as multi-color and label-free cellular imaging. We show that Ultrack achieves state-of-the-art performance on the Cell Tracking Challenge and demonstrates superior accuracy in tracking densely packed embryonic cells over extended periods. Moreover, we propose an approach to tracking validation via dual-channel sparse labeling that enables high-fidelity ground truth generation, pushing the boundaries of long-term cell tracking assessment. Our method is freely available as a Python package with Fiji and napari plugins and can be deployed in a high-performance computing environment, facilitating widespread adoption by the research community.

developmental biology↗

bioRxiv2023

Integrated multi-omics approach reveals the role of SPEG in skeletal muscle biology including its relationship with myospryn complex

Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy. Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, and calcium mishandling in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes. We identified that SPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and SPEG deficiency results in myospryn complex abnormalities. In addition, transcriptional and protein profiles of SPEG-deficient muscle revealed defective mitochondrial function including aberrant accumulation of enlarged mitochondria on electron microscopy. Furthermore, SPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. On analyzing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction and peroxisome proliferator-activated receptors signaling, which may be due to defective triad and mitochondrial abnormalities. In summary, we have elucidated the critical role of SPEG in triad as it works closely with myospryn complex, phosphorylates JPH2 and RyR1, and demonstrated that its deficiency is associated with mitochondrial abnormalities. This study emphasizes the importance of using multi-omics techniques to comprehensively analyze the molecular anomalies of rare diseases. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/538136v1_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@bc3cbborg.highwire.dtl.DTLVardef@37195dorg.highwire.dtl.DTLVardef@1624caeorg.highwire.dtl.DTLVardef@985a2c_HPS_FORMAT_FIGEXP M_FIG C_FIG We have previously linked mutations in SPEG (striated preferentially expressed protein) with a recessive form of centronuclear myopathy and/or dilated cardiomyopathy and have characterized a striated muscle-specific SPEG-deficient mouse model that recapitulates human disease with disruption of the triad structure and calcium homeostasis in skeletal muscles. In this study, we applied multi-omics approaches (interactomic, proteomic, phosphoproteomic, and transcriptomic analyses) in the skeletal muscles of SPEG-deficient mice to assess the underlying pathways associated with the pathological and molecular abnormalities. O_LISPEG interacts with myospryn complex proteins (CMYA5, FSD2, RyR1), and its deficiency results in myospryn complex abnormalities. C_LIO_LISPEG regulates RyR1 phosphorylation at S2902, and its loss affects JPH2 phosphorylation at multiple sites. C_LIO_LISPEG and SPEG{beta} have different interacting partners suggestive of differential function. C_LIO_LITranscriptome analysis indicates dysregulated pathways of ECM-receptor interaction and peroxisome proliferator-activated receptor signaling. C_LIO_LIMitochondrial defects on the transcriptome, proteome, and electron microscopy, may be a consequence of defective calcium signaling. C_LI

molecular biology↗

bioRxiv2022

The Lamin A/C Ig-fold undergoes cell density-dependent changes that alter epitope accessibility

Lamins A/C are nuclear intermediate filament proteins that are involved in diverse cellular mechanical and biochemical functions. Here, we report that recognition of Lamins A/C by a commonly used antibody (JOL-2) that binds the Lamin A/C Ig-fold and other antibodies targeting similar epitopes is highly dependent on cell density, even though Lamin A/C protein levels do not change with cell density. The density-dependent Lamin A/C labeling was distinct from previously reported differential apico-basal labeling, which was independent of cell density. Comparison of the density-dependent labeling effects of antibodies recognizing different Lamin A/C epitopes suggests that the effect is caused by partial unfolding or masking of the CE and/or EF loops of the Ig-fold in response to cell spreading. Seeding cells on micropatterned surfaces with different areas confirmed that increased cell spreading resulted in reduced Lamin A/C labeling with the JOL-2 antibody. Surprisingly, JOL-2 antibody labeling was insensitive to depolymerization of cytoskeletal filaments or disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex. Although the density-dependent changes of the Ig-fold did not alter nuclear stiffness or nucleo-cytoskeletal force transmission, they may nonetheless modulate interaction with lamin binding partners and thereby affect cellular functions. Taken together, our results point to a previously unrecognized change in the Lamin A/C Ig-fold that affects recognition by the JOL-2 antibody. These findings are not only important for the interpretation of immunofluorescence data for Lamin A/C, but also raise the intriguing prospect that the conformational changes may play a role in Lamin A/C mediated cellular function.

cell biology↗

bioRxiv2022

The KASH5 protein involved in meiotic chromosomal movements is a novel dynein activating adaptor

Dynein harnesses ATP hydrolysis to move cargo on microtubules in multiple biological contexts. Dynein meets a unique challenge in meiosis by moving chromosomes tethered to the nuclear envelope to facilitate homolog pairing essential for gametogenesis. Though processive dynein motility requires binding to an activating adaptor, the identity of the activating adaptor required for dynein to move meiotic chromosomes is unknown. We show that the meiosis-specific nuclear-envelope protein KASH5 is a dynein activating adaptor: KASH5 directly binds dynein using a mechanism conserved among activating adaptors and converts dynein into a processive motor. We map the dynein-binding surface of KASH5, identifying mutations that abrogate dynein binding in vitro and disrupt recruitment of the dynein machinery to the nuclear envelope in cultured cells and mouse spermatocytes in vivo. Our study identifies KASH5 as the first transmembrane dynein activating adaptor and provides molecular insights into how it activates dynein during meiosis.

cell biology↗

bioRxiv2022

Significant Broad Spectrum Antiviral activity of Bi121 Against Different Variants of SARS-CoV-2

The SARS-CoV-2 pandemic infected 343 million people with over 5.59 million deaths. New mutated lineages of SARS-CoV-2 such as Omicron are evolving faster. Broad-spectrum viral inhibitors that block the initial stage of infection by reducing virus proliferation and disease severity is an unmet global medical need. We studied Bi121, a standardized polyphenolic-rich compound isolated from Pelargonium sidoides, against recombinant Vesicular Stomatitis Virus (rVSV)-pseudotyped SARS-CoV-2S (spike) that represent mutations in the spike protein of six different variants of SARS-CoV-2. Bi121 was effective in neutralizing all six rVSV-{Delta}G-SARS-CoV-2S variants expressing different mutations. The antiviral activity of Bi121 was then assessed against three variants of SARS-CoV-2 (USA WA1/2020, Hongkong/VM20001061/2020, B.1.167.2 (Delta)) using RT-qPCR and plaque assays in two different cell lines (Vero cells and HEK-ACE2). Bi121 showed significant activity toward all the three variants tested, suggesting a broad-spectrum activity.

microbiology↗