Biology subjects

Sato, A.

Publications and source records attributed to Sato, A..

At least 19 recordsLinked to original sources

bioRxiv2026

Identification of Novel Gamma Radiation-Responsive Genes in the Thiosulfate-Oxidizing Bacterium Limnobacter thiooxidans

Ionizing radiation induces DNA damage and oxidative stress; however, the genes and molecular mechanisms involved in bacterial stress responses have not been sufficiently identified. In this study, we used Limnobacter thiooxidans strain CS-K2, which is the closest relative to the bacteria detected in torus room water at the Fukushima Daiichi Nuclear Power Plant according to 16S rRNA gene sequences, and evaluated its response to {gamma}-ray irradiation using integrated transcriptomic and proteomic analyses. We identified three previously uncharacterized genes (LT3105, LT3115, and LT3126) that were strongly induced at the mRNA and protein levels. These genes exhibited low basal expression but were markedly upregulated by {gamma}-ray irradiation. Notably, LT3126 encodes a protein containing VIT (vault protein inter--trypsin) and VWA (von Willebrand factor type A) domains and showed the strongest induction. Overexpression of LT3126 increased survival after 500 Gy irradiation by approximately 200-fold compared with the control bacteria, demonstrating a direct contribution to survival under high-dose stress. Comparative genomic analysis showed that these genes are not widely conserved across bacteria but are unevenly distributed among specific lineages. Taken together, this study identified a novel set of {gamma}-ray-responsive genes and demonstrated a functional role for LT3126 in radiation resistance, providing new insights into molecular adaptation in radiation-associated environments. IMPORTANCEWe identified a novel set of {gamma}-ray-responsive genes (LT3105, LT3115, and LT3126) in the non-model bacterium Limnobacter thiooxidans. These genes are located in relatively close genomic proximity and are coordinately induced upon irradiation, suggesting a shared functional role in stress response. Overexpression of LT3126 increased survival by approximately 200-fold after 500 Gy irradiation compared with the control bacteria, demonstrating a substantial contribution to survival under high-dose stress. These genes were also induced by heat shock and oxidative stress, indicating that their function extends beyond radiation-specific responses to broader environmental stress adaptation. Consistent with this, comparative genomic analysis showed that these genes are not widely conserved across bacteria but are unevenly distributed among specific lineages. Taken together, these findings highlight previously unrecognized molecular strategies that may support bacterial survival in radiation-associated environments.

microbiology↗

bioRxiv2026

Integrated in vivo and transcriptomic analyses of lethal Oropouche virus infection reveal suppression of pathogenic host responses by antiviral therapy

Oropouche virus (OROV) is an emerging arbovirus responsible for large outbreaks of febrile illness in Central and South America, with increasing reports of severe neurological disease and fatal outcomes. Despite its growing public health impact, no approved antiviral therapies or vaccines are currently available. Here, we show that favipiravir, a broad-spectrum nucleoside analogue, robustly suppresses OROV replication and disease in vivo. In a lethal Syrian hamster model, favipiravir treatment provided complete protection against OROV infection, preventing viral dissemination to peripheral organs and the central nervous system, and remained highly effective when administration was initiated after infection. In contrast, insufficient antiviral control resulted in viral neuroinvasion and fatality. To define host responses associated with OROV pathogenesis and their modulation by antiviral therapy, we performed transcriptomic profiling of liver and brain tissues. OROV infection induced interferon-driven inflammatory programs accompanied by marked disruption of metabolic and tissue homeostatic pathways, whereas these transcriptional signatures were largely abrogated by favipiravir treatment. Together, our findings identify favipiravir as a potent antiviral candidate against OROV and provide the first in vivo, tissue-resolved transcriptomic framework of OROV infection, linking effective viral suppression with the prevention of neuroinvasion and pathogenic host responses. These results highlight antiviral intervention as a viable strategy to mitigate OROV-associated disease and mortality.

microbiology↗

bioRxiv2025

Quantitative manipulation of the photoperiodic flowering by a small-molecule clock modulator

Photoperiodism, a seasonal response mechanism that relies on day-length measurement by the circadian clock, is a major regulator of flowering time 1. The external coincidence model proposes that the alignment between the internal circadian phase and external light signals triggers photoperiodic responses 2. It has been challenging to establish robust models for the quantitative relationship between clock and flowering time, due to a lack of tools to modulate clock quantitatively. Here, using a circadian period-lengthening small molecule, we demonstrated the quantitative modulation of the critical day length for flowering in monocots.

plant biology↗

bioRxiv2025

SNPD-siKRAS: siRNA specifically inhibits KRAS with a single-nucleotide mutation

Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) is the most frequently mutated gene associated with pancreatic cancer. However, targeting mutated KRAS without affecting the wild-type KRAS expression by conventional chemotherapy is challenging, because KRAS protein is considered to be undruggable due to the lack of surface structures for drug binding. Here, we developed a single-nucleotide polymorphism-distinguishable small interfering RNA (SNPD-siRNA) that suppresses the expression of mutated KRAS without affecting the wild type KRAS expression through discrimination of single-nucleotide differences using RNA interference technology. In two- and three-dimensional cultures of human pancreatic cancer-derived cell lines, SNPD-siKRAS significantly reduced the mutated KRAS expression, and suppressed the cell proliferation by inhibiting the activity of MAPK/PI3K pathway. Furthermore, the xenograft experiments using mice revealed that the growth of implanted pancreatic cancer-derived cells were suppressed by the SNPD-siKRAS. Thus, this technology may provide a therapeutic platform for personalized genomic medicine that can identify the single nucleotide mutations in the disease-causing genes.

molecular biology↗

bioRxiv2025

Twinfilin-1 phosphorylation in reelin signaling regulates actin dynamics and spine development

Reelin is an extracellular glycoprotein essential for neuronal migration, spine development, and synaptic plasticity. Impaired reelin signaling is linked to neurological disorders, including schizophrenia and autism. While reelin mutant (reeler) mice exhibit behavioral deficits associated with impaired spine formation, the underlying molecular mechanisms remain unclear. We identified Twinfilin-1 (Twf1) as a downstream effector of reelin signaling via phosphoproteomic analysis, based on its reduced tyrosine phosphorylation in reeler mice. We found that Src regulated Twf1 phosphorylation at tyrosine 309, and reelin stimulation increased Twf1 phosphorylation in neurons, an effect blocked by the Src inhibitor PP2. A phospho-resistant Twf1 mutant (Twf1 Y309F) showed reduced capping protein binding and a lower F/G-actin ratio. Twf1Y309F mice exhibited cognitive deficits, reduced spine density, smaller spine head size, and a decreased F/G-actin ratio in synaptosomes. These findings highlight Twf1 phosphorylation as a key component of reelin signaling involved in actin remodeling and spine development.

neuroscience↗

bioRxiv2025

Proteome-level robustness and the role of a histone-like protein during acute heat shock in the hyperthermophilic archaeon Pyrococcus furiosus

The hyperthermophilic archaeon Pyrococcus furiosus thrives in extreme temperatures and exhibits a complex response to heat shock. However, the regulatory dynamics of genetic information during heat shock remain poorly understood. In this study, we exposed P. furiosus (cultured at 90{degrees}C) to acute heat shock by boiling (101-102{degrees}C) and analyzed its transcriptomic and proteomic responses. The levels of 16S and 23S rRNAs and of total tRNA were decreased by approximately 50%, and pre-tRNA splicing was inhibited, indicating suppression of translation. By contrast, approximately 90% of the proteome remained stable, underscoring the robustness of existing proteins. However, the transcriptome exhibited widespread alterations with limited correlation to the proteome (correlation coefficient r = 0.32), except for a few key proteins. These proteins included PF1883 (small heat shock protein), PF1385 (uracil-DNA glycosylase), and PF1616 (inositol-1-phosphate synthase), which are involved in protein chaperoning, stress-related metabolite synthesis, and DNA repair, respectively. Additionally, PF0624, previously annotated as a hypothetical protein, was identified as a putative histone motif-containing protein. Experimental evidence suggests that PF0624 may contribute to chromatin formation via archaeal histones in P. furiosus. In summary, our findings reveal that P. furiosus responds to acute heat shock by maintaining protein stability, suppressing translation, limiting genomic damage, and potentially compacting genomic DNA into archaeal chromatin. IMPORTANCEHyperthermophilic archaea, such as Pyrococcus furiosus, thrive in extreme environments where the temperatures may reach up to 100{degrees}C. However, the precise mechanisms by which these organisms protect their genomic DNA from heat-induced damage remain incompletely understood. In this study, we propose that PF0624, a histone-like protein that is transcriptionally induced and translated in response to acute heat shock, is critical in stabilizing archaeal chromatin structure through histone-mediated mechanisms. Our results highlight the sophisticated molecular strategies employed by P. furiosus to survive extreme thermal stress.

molecular biology↗

bioRxiv2025

Simple and quantitative detection of double-stranded RNA as a signature of pan-virus infections using a luciferase-based biosensor

Viral infections produce double-stranded RNA (dsRNA) during replication, which trigger host innate immune responses. Immunoassays using anti-dsRNA antibodies have been widely employed to detect viral dsRNA. In this study, we used a luciferase-based dsRNA biosensor which consists of protein kinase R (PKR)-derived dsRNA binding domains fused to split luciferase subunits. Here, we demonstrate the use of the dsRNA biosensor to measure viral dsRNA in RNA specimens extracted from cells infected with Japanese encephalitis virus (JEV). Moreover, the biosensor reacts to a broad-spectrum of dsRNAs from infection with representatives of various viral families including positive- and negative-sense single-stranded RNA (ssRNA) viruses, dsRNA viruses, and DNA viruses. We validated the specific interaction between the dsRNA biosensor and viral RNA including subgenomic flavivirus RNA (sfRNA) through RNA immunoprecipitation. Additionally, we observed luminescence signals directly from lysates of JEV-infected cells after cell lysis and phase separation with Triton X-114. Finally, we used the biosensor to assess the activity of antiviral compounds. In summary, our results demonstrate that the luciferase-based dsRNA biosensor offers a simple, homogeneous, and high-throughput platform for quantifying viral replication, presenting a promising alternative to antibody-based dsRNA detection methods.

microbiology↗

bioRxiv2024

Single-step in vitro ribosome reconstitution mediated by two GTPase factors, EngA and ObgE

When bacterial ribosomes are assembled in vitro, manipulation of incubation temperature and magnesium ion concentration have been an essential procedure, which is a crucial step for the assembly of active large subunits. The present study tackles with this issue to develop a single-step procedure, which can be performed in a near-physiological condition, where cell-free protein synthesis is active. We found that GTPase factors EngA and ObgE can complement the changes in temperature and magnesium ion concentrations. In the presence of these factors, both the ribosome assembly and translation processes were successfully integrated in the reconstituted cell-free protein synthesis system. Furthermore, we found that these GTPase factors can reassemble the ribosomes to an active state, whose structure was disrupted by EDTA chelation of magnesium ions, indicating that these two factors can reversibly induce the ribosome structure to an intact state. The findings are essential for the bottom-up construction of synthetic cells.

biochemistry↗

bioRxiv2024

CRISPR activation of Tfeb, a master regulator of autophagy and lysosomal biogenesis, in osteoblast lineage cells increases bone mass and strength

Autophagy is a recycling pathway in which damaged or dysfunctional proteins, protein aggregates, and organelles are delivered to lysosomes for degradation. Insufficiency of autophagy is thought to contribute to several age-related diseases including osteoporosis. Consistent with this, elimination of autophagy from the osteoblast lineage reduces bone formation and causes low bone mass. However, whether increasing autophagy would benefit bone health is unknown. Here, we increased expression of the endogenous Transcription Factor EB gene (Tfeb) in osteoblast lineage cells in vivo via CRISPR activation. Tfeb overexpression stimulated autophagy and lysosomal biogenesis in osteoblasts. Tfeb overexpressing male mice displayed a robust increase in femoral and vertebral cortical thickness at 4.5 months of age. Histomorphometric analysis revealed that the increase in femoral cortical thickness was due to increased bone formation at the periosteal surface. Tfeb overexpression also increased femoral trabecular bone volume. Consistent with these results, bone strength was increased in Tfeb overexpressing mice. Female Tfeb overexpressing mice also displayed a progressive increase in bone mass over time and at 12 months of age had high cortical thickness and trabecular bone volume. This increase in vertebral trabecular bone volume was due to elevated bone formation. Osteoblastic cultures showed that Tfeb overexpression increased proliferation and osteoblast formation. Overall, these results demonstrate that stimulation of autophagy in osteoblast lineage cells promotes bone formation and strength and may represent an effective approach to combat osteoporosis.

physiology↗

bioRxiv2024

Chemical genetics reveals cross-activation of plant developmental signaling by the immune peptide-receptor pathway

Cells sense and integrate multiple signals to coordinate development and defence. A receptor-kinase signaling pathway for plant stomatal development shares components with the immunity pathway. The mechanism ensuring their signal specificities remains unclear. Using chemical genetics, here we report the identification of a small molecule, kC9, that triggers excessive stomatal differentiation by inhibiting the canonical ERECTA receptor-kinase pathway. kC9 binds to and inhibits the downstream MAP kinase MPK6, perturbing its substrate interaction. Strikingly, activation of immune signaling by a bacterial flagellin peptide nullified kC9s effects on stomatal development. This cross-activation of stomatal development by immune signaling depends on the immune receptor FLS2 and occurs even in the absence of kC9 if the ERECTA-family receptor population becomes suboptimal. Furthermore, proliferating stomatal-lineage cells are vulnerable to the immune signal penetration. Our findings suggest that the signal specificity between development and immunity can be ensured by MAP Kinase homeostasis reflecting the availability of upstream receptors, thereby providing a novel view on signal specificity.

plant biology↗

bioRxiv2024

Genome-wide epitope identification with single-amino-acid resolution via high-throughput and unbiased peptide analysis

Antibodies are extensively used in biomedical research, clinical fields, and disease treatment. However, to enhance the reproducibility and reliability of antibody-based experiments, it is crucial to have a detailed understanding of the antibodys target specificity and epitope. In this study, we developed a high-throughput and precise epitope analysis method, DECODE (Decoding Epitope Composition by Optimized-mRNA-display, Data analysis, and Expression sequencing). This method allowed identifying patterns of epitopes recognized by monoclonal or polyclonal antibodies at single amino acid resolution and predicted cross-reactivity against the entire protein database. By applying the obtained epitope information, it has become possible to develop a new 3D immunostaining method that increases the penetration of antibodies deep into tissues. Furthermore, to demonstrated the applicability of DECODE to more complex blood antibodies, we performed epitope analysis using serum antibodies from mice with experimental autoimmune encephalomyelitis (EAE). As a result, we were able to successfully identify an epitope that matched the sequence of the peptide inducing the disease model without relying on existing antigen information. These results demonstrate that DECODE can provide high-quality epitope information, improve the reproducibility of antibody-dependent experiments, diagnostics and therapeutics, and contribute to discover pathogenic epitopes from antibodies in the blood.

bioengineering↗

bioRxiv2024

Comprehensive analysis of insertion sequences within rRNA genes of CPR bacteria and biochemical characterization of a homing endonuclease encoded by these sequences

The Candidate Phyla Radiation (CPR) represents an extensive bacterial clade comprising primarily uncultured lineages and is distinguished from other bacteria by a significant prevalence of insertion sequences (ISs) within their rRNA genes. However, our understanding of the taxonomic distribution and characteristics of these ISs remains limited. In this study, we used a comprehensive approach to systematically determine the nature of the rRNA ISs in CPR bacteria. The analysis of hundreds of rRNA gene sequences across 65 CPR phyla revealed that ISs are present in 48% of 16S rRNA genes and 82% of 23S rRNA genes, indicating a broad distribution across the CPR clade, with exceptions in the 16S and 23S rRNA genes of Saccharibacteria and the 16S rRNA genes of Peregrinibacteria. Over half the ISs display a group-I-intron-like structure, whereas specific 16S rRNA gene ISs display features reminiscent of group II introns. The ISs frequently encode proteins with homing endonuclease (HE) domains, centered around the LAGLIDADG motif. The LAGLIDADG HE (LHE) proteins encoded by the rRNA ISs of CPR bacteria predominantly have a single-domain structure, deviating from the usual single- or double-domain configuration observed in typical prokaryotic LHEs. Experimental analysis of one LHE protein, I-ShaI from Ca. Shapirobacteria, confirmed that its endonuclease activity targets the DNA sequence of its insertion site, and chemical cross-linking experiments demonstrated its capacity to form homodimers. These results provide robust evidence supporting the hypothesis that the explosive proliferation of rRNA ISs in CPR bacteria was facilitated by mechanisms involving LHEs. IMPORTANCEInsertion sequences (ISs) in rRNA genes are relatively limited and infrequent in standard bacteria. With a comprehensive bioinformatic analysis, we show that in CPR bacteria, which are characterized by a high frequency of ISs, these ISs occur in 48% of 16S rRNA genes and 82% of 23S rRNA genes. We also report the systematic and biochemical characterization of the LAGLIDADG homing endonucleases (LHEs) encoded by these ISs in the first such analysis of the CPR bacteria. This study significantly extends our understanding of the phylogenetic positions of rRNA ISs within CPR bacteria and the biochemical features of their LHEs.

molecular biology↗

bioRxiv2023

IMPROVING ANTIBODY AFFINITY USING LABORATORYDATA WITH LANGUAGE MODEL GUIDED DESIGN

AO_SCPLOWBSTRACTC_SCPLOWProtein design involves navigating vast sequence spaces to discover sequences with desired traits. Language models (LMs) pretrained on universal protein datasets have shown potential to make this search space tractable. However, LMs trained solely on natural sequences have limitations in creating proteins with novel functions. In this work, we used a combination of methods to finetune pretrained LMs on laboratory data collected in an anti-CD40L single domain antibody library campaign to develop an ensemble scoring function to model the fitness landscape and guide the design of new antibodies. Laboratory experiments confirmed improved CD40L affinity in the designed antibodies. Notably, the designs improved the affinities of four antibodies, originally ranging from 1 nanomolar to 100 picomolar, all to below 25 picomolar, approaching the limit of detection. This work is a promising step towards realizing the potential of LMs to leverage laboratory data to develop improved treatments for diseases.

synthetic biology↗

bioRxiv2023

Combination therapy with oral antiviral and anti-inflammatory drugs improves the efficacy of delayed treatment in severe COVID-19

Pulmonary infection with SARS-CoV-2 stimulates host immune responses and can also result in the progression of dysregulated and critical inflammation. Throughout the pandemic, the management and treatment of COVID-19 has been continuously updated with a range of antiviral drugs and immunomodulators. Monotherapy with oral antivirals has proven to be effective in the treatment of COVID-19. However, the treatment should be initiated in the early stages of infection to ensure beneficial therapeutic outcomes, and there is still room for further consideration on therapeutic strategies using antivirals. Here, we show that the oral antiviral ensitrelvir combined with the anti-inflammatory corticosteroid methylprednisolone has higher therapeutic effects and better outcomes in a delayed dosing model of SARS-CoV-2 infected hamsters compared to the monotherapy with ensitrelvir or methylprednisolone alone. Combination therapy with these drugs improved respiratory conditions and the development of pneumonia in hamsters even when the treatment was started after 2 days post infection. The combination therapy led to a differential histological and transcriptomic pattern in comparison to either of the monotherapies, with reduced lung damage and down-regulated expressions of genes involved in inflammatory response. Furthermore, we found that the combination treatment is effective in infection with both highly pathogenic delta and circulating omicron variants. Our results demonstrate the advantage of combination therapy with antiviral and corticosteroid drugs in COVID-19 treatment. Since both drugs are available as oral medications, this combination therapy could provide a clinical and potent therapeutic option for COVID-19.

microbiology↗

bioRxiv2023

A multiscale computational framework for the development of spines in molluscan shells

From mathematical models of growth to computer simulations of pigmentation, the study of shell formation has given rise to an abundant number of models, working at various scales. Yet, attempts to combine those models have remained sparse, due to the challenge of combining categorically different approaches. In this paper, we propose a framework to streamline the process of combining the molecular and tissue scales of shell formation. We choose these levels as a proxy to link the genotype level, which is better described by molecular models, and the phenotype level, which is better described by tissue-level mechanics. We also show how to connect observations on shell populations to the approach, resulting in collections of molecular parameters that may be associated with different populations of real shell specimens. The approach is as follows: we use a Quality-Diversity algorithm, a type of black-box optimization algorithm, to explore the range of concentration profiles emerging as solutions of a molecular model, and that define growth patterns for the mechanical model. At the same time, the mechanical model is simulated over a wide range of growth patterns, resulting in a variety of spine shapes. While time-consuming, these steps only need to be performed once and then function as look-up tables. Actual pictures of shell spines can then be matched against the list of existing spine shapes, yielding a potential growth pattern which, in turn, gives us matching molecular parameters. The framework is modular, such that models can be easily swapped without changing the overall working of the method. As a demonstration of the approach, we solve specific molecular and mechanical models, adapted from available theoretical studies on molluscan shells, and apply the multiscale framework to evaluate the characteristics of spines from three distinct populations of Turbo sazae. Author summaryConnecting genotype to phenotype is a fundamental goal in developmental biology. While many studies examine this link in model organisms for which gene regulatory networks are well known, for non-model organisms, different techniques are required, and multiscale computational modeling offers a promising direction. In this paper, we develop a framework linking molecular-scale interactions to tissue-level growth and mechanics to organism-level characteristics in order to investigate spine formation in T. sazae, a species of mollusc that displays remarkable phenotypic plasticity in spine form. Our analysis uncovers a subtle but statistically significant difference in spine form between shell specimens collected from three different localities in Japan. Moreover, by tracing the difference in form through parametric differences in the multiscale framework, we provide mechanistic insight as to how environmental differences may translate to a change in form. The methodology we present may readily be extended to more detailed modeling of this system, and the conceptual framework is amenable for multiscale analysis in other systems.

systems biology↗

bioRxiv2023

Effect of acetic acid bacteria colonization on oviposition and feeding site choice in Drosophila suzukii and its related species

Oviposition site choice has a large impact on offspring performance. Unlike other vinegar flies that colonize decaying fruits, Drosophila suzukii lay eggs into hard ripening fruits by using their enlarged and serrated ovipositors (oviscapts). This behavior has an advantage over other species by providing access to the host fruit earlier and avoiding competition. However, the larvae are not fully adapted to a low-protein diet, and the availability of intact healthy fruits is seasonally restricted. Thus, to investigate oviposition site preference for microbial growth in this species, we conducted an oviposition assay using single species of commensal Drosophila acetic acid bacteria, Acetobacter and Gluconobacter. The oviposition site preferences for media with or without bacterial growth were quantified in multiple strains of D. suzukii and its closely related species, D. subpulchrella and D. biarmipes, and a typical fermenting-fruit consumer, D. melanogaster. Our comparisons demonstrated a continuous degree of preference for sites with Acetobacter growth both within and across species, suggesting that the niche separation is notable but not complete. The preference for Gluconobacter showed large variations among replicates and no clear differences between the strains. In addition, the lack of interspecific differences in feeding site preference for Acetobacter-containing media implies that the interspecific divergence in oviposition site preference occurred independently from the feeding site preference. Our oviposition assays measuring the preference of multiple strains from each fly species for acetic acid bacteria growth revealed intrinsic properties of shared resource usage among these fruit fly species.

evolutionary biology↗

bioRxiv2023

Diversification of Polynucleotide Kinase Clp1 Family Proteins and Their Possible Origins in Eukaryotic Evolution

The Clp1 family proteins, consisting of the Clp1 and Nol9/Grc3 groups, have polynucleotide kinase (PNK) activity at the 5' end of RNA strands and are important enzymes in the processing of some precursor RNAs. However, it remains unclear how this enzyme family diversified in the eukaryotes. We performed a large-scale molecular evolutionary analysis of the full-length genomes of 358 eukaryotic species and identified a group of protist proteins that we consider to be the evolutionary origin of Clp1 family proteins. First, we detected an average of 4.2 Clp1 family genes in members of in the protist phylum Euglenozoa, arising from gene duplication. For example, in Trypanosoma brucei, there are three genes of the Clp1 group and one gene of the Nol9/Grc3 group. In the Clp1 group proteins encoded by these three genes, the C-terminal domains have been replaced by unique characteristics domains, so we designated these proteins Tb-Clp1-t1, Tb-Clp1-t2, and Tb-Clp1-t3. Experimental validation showed that only Tb-Clp1-t2 has PNK activity against RNA strands. In a phylogenetic analysis of the PNK domain, Tb-Clp1-t2 mapped to the earliest position on the tree. Interestingly, Tb-Clp1-t1, for which no PNK activity was detected, was located on the phylogenetic tree near fungal Saccharomyces cerevisiae Clp1, which also lacks PNK activity. The analysis also revealed that in the higher eukaryotes, such as humans and plants, the Clp1 proteins diversified with the creation of isoforms by alternative splicing.

evolutionary biology↗

bioRxiv2022

2-Thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes significant morbidity and mortality worldwide, seriously impacting not only human health but also the global economy. Furthermore, over 1 million cases of newly emerging or re-emerging viral infections, specifically dengue virus (DENV), are known to occur annually. Because no virus-specific and fully effective treatments against these and many other viruses have been approved, they continue to be responsible for large-scale epidemics and global pandemics. Thus, there is an urgent need for novel, effective therapeutic agents. Here, we identified 2-thiouridine (s2U) as a broad-spectrum antiviral nucleoside analogue that exhibited antiviral activity against SARS-CoV-2 and its variants of concern, including the Delta and Omicron variants, as well as a number of other positive-sense single-stranded RNA (ssRNA+) viruses, including DENV. s2U inhibits RNA synthesis catalyzed by viral RNA-dependent RNA polymerase, thereby reducing viral RNA replication, which improved the survival rate of mice infected with SARS-CoV-2 or DENV in our animal models. Our findings demonstrate that s2U is a potential broad-spectrum antiviral agent not only against SARS-CoV-2 and DENV but other ssRNA+ viruses.

microbiology↗