Biology subjects

Aoki, S.

Publications and source records attributed to Aoki, S..

At least 19 recordsLinked to original sources

bioRxiv2026

A Proof-of-Concept Study on Attached Spirulina Cultivation Under Microgravity and Partial Gravity Aboard the ISS

Microalgal attached cultivation circumvents gas-liquid separation issues of liquid-suspended cultivation, yet performance under reduced gravity remains unevaluated. As a proof-of-concept, we evaluated Arthrospira platensis (Spirulina) cultivation under artificial 1G, 1/6G, and microgravity ({micro}G) on the International Space Station. Spirulina expanded without cell detachment, medium floating, or component separation, with relative radial growth rates of 0.28%0.5 day-1 (1G), 0.22%0.5 day-1 (1/6G), and 0.17-0.21%0.5 day-1 ({micro}G), demonstrating feasibility in space.

bioengineering↗

bioRxiv2026

Hypoxia reduces induced LRIG1 protein despite sustained mRNA induction in colorectal cancer organoids

LRIG1 is a negative regulator of receptor tyrosine kinase (RTK) signaling that promotes tumor suppression by driving degradation of EGFR and other RTKs. Inducing LRIG1 expression has therefore been proposed as a strategy to limit cancer cell survival under hypoxia. However, whether hypoxia itself affects LRIG1 expression remains unclear. Here, we investigated how hypoxia affects LRIG1 expression and protein abundance in human cancer datasets and colorectal cancer organoids. Analysis of The Cancer Genome Atlas data across gastrointestinal and other cancers revealed an inverse association between LRIG1 mRNA expression and a hypoxia gene signature that persisted after adjustment for global gene expression. We previously showed that BMPR inhibition induces LRIG1 and suppresses colorectal cancer organoid growth through LRIG1. Under hypoxia, this growth inhibition in colorectal cancer organoids was attenuated, and LRIG1 protein accumulation was reduced despite sustained mRNA induction. Pre-induced LRIG1 protein declined within 3 h of hypoxic exposure in organoids, and ectopically expressed LRIG1 similarly decreased in HEK293 cells. Pharmacological HIF1 inhibition did not prevent LRIG1 protein loss under hypoxia, whereas HIF1 stabilization did not reproduce it under normoxia, suggesting limited HIF1 involvement. Bafilomycin A1 restored LRIG1 protein levels, whereas chloroquine and the proteasome inhibitor MG132 did not, implicating a bafilomycin A1-sensitive lysosomal process. Notably, the hypoxia-induced decrease in LRIG1 was not accompanied by a decrease in total EGFR. These findings suggest that hypoxia limits LRIG1 protein induction, potentially constraining strategies that rely on LRIG1 induction in cancer treatment.

biochemistry↗

bioRxiv2026

Arabidopsis thaliana ACTIN DEPOLYMERIZING FACTORs are novel susceptibility factors for Colletotrichum higginsianum

Colletotrichum higginsianum (Ch) is a hemibiotrophic fungal pathogen that infects Brassicaceae plants, including Arabidopsis thaliana. The molecular mechanisms underlying the Ch-A. thaliana interaction are not fully understood. Particularly, the susceptibility factor against Ch infection remains to be determined. Here, we report that A. thaliana ACTIN DEPOLYMERIZING FACTORs (ADFs), ancient proteins that regulate the organization and dynamics of actin filaments (AFs), function as susceptibility factors during Ch infection. Among 11 ADFs encoded in A. thaliana genome, subclass I ADFs that include ADF1, -2, -3, and -4, express throughout the plant. We found that knockout mutant of ADF4 and transgenic plants in which the expression of all of subclass I members is suppressed (ADF1-4Ri) exhibited increased resistance to Ch. Cytological analyses revealed that both Ch penetration and secondary hyphae formation were suppressed in adf4 and ADF1-4Ri. This enhanced resistance was associated with suppression of Ch-induced AF fragmentation. In addition, we found that PENETRATION 2 (PEN2) plays a critical role in the Ch resistance in adf4 and ADF1-4Ri. Our findings suggest that subclass I ADFs promote AF fragmentation during Ch infection, thereby suppressing PEN2-associated mitochondria accumulation at Ch entry sites. Together, these results raise the possibility that Ch exploits host ADF-dependent actin regulation to facilitate successful infection.

plant biology↗

bioRxiv2026

Evolutionary trade-offs between growth and reproduction under obesogenic conditions: sex-biased skeletal and gonadal maturation in mice

Adolescence is a brief period during which finite energy resources are reallocated from linear growth toward reproductive maturation. Rising childhood obesity and earlier onset of puberty suggest that modern, energy rich diets may distort these evolved energy allocation rules, but causal mechanisms remain unclear. Here, we expose male and female wild-type and leptin receptor deficient (Db/Db) to either high fat or normal chow diets. We longitudinally analyze metabolic, skeletal, gonadal, endocrine and insulin-receptor phenotypes from 4-10 weeks of age (sexual maturation window in mice). In WT males, HFDs increased adiposity and impaired glucose tolerance, and selectively remodeled joint morphology, advanced gonadal maturation, and shifted insulin receptor expression from growth plates to testes. Together, these changes indicate a rebalancing of energy use toward reproduction at the expense of skeletal and metabolic health. WT females showed subtler systemic metabolic disruption but clear diet-responsive changes in growth plate and ovarian maturation. Our findings indicate that energy-rich diets during adolescence shift evolved allocation rules to prioritize reproductive readiness over skeletal robustness in a sex-dependent manner, with potential consequences for precocious puberty and bone health in humans.

evolutionary biology↗

bioRxiv2026

A fungal phosphate starvation regulator gates virulence to prioritize nutrient adaptation in response to host phosphate status

Plant-associated microbes must constantly balance environmental adaptation with virulence to survive in fluctuating ecosystems, yet the molecular mechanisms coupling these processes remain poorly understood. Here, we identify NUTRIENT-DEPENDENT FACILITATOR OF COLONIZATION1 (NFC1), a virulence factor in a conditionally pathogenic Colletotrichum tofieldiae strain, whose expression is tightly regulated by both temperature and phosphate availability. Leveraging plant phosphate starvation response (PSR) mutants and direct phosphate supplementation to host plants, we demonstrate that NFC1 expression is driven by the internal phosphate status of the host rather than environmental availability alone. Notably, the fungal PSR regulator CtPHO4 represses NFC1 and virulence during phosphate starvation, while simultaneously activating canonical fungal PSR-related genes. Conversely, under phosphate sufficiency, NFC1 is strongly induced and promotes infection, potentially by modulating the host circadian clock system. This study uncovers a molecular link between metabolic adaptation and virulence programming, providing a conceptual framework for predicting disease dynamics under changing environments.

microbiology↗

bioRxiv2025

Consolidation of a recurrent choice pattern into a fixed action schema requires the orbitofrontal cortex

Our actions are crystallized by repetition, warranting the efficiency, reproducibility and stability of decisions. Unlike a habit that is formally defined as insensitive to reward value, such persistency in choice can still be shaped and executed in a goal-directed manner, which underlies many volitional behaviors in animals. Yet, largely due to the absence of an established procedure that accesses non-habitual but persistent patterns of choice in animal models, empirical findings that identify its neural substrates are lacking. Using a cost-benefit conflicting decision paradigm in rodents, we here introduce an experimental procedure involving extensive decision opportunities in a fixed contingency, whereby mice acquire a recurrent pattern of choice and shape it into a fixed schema of goal-directed action to guide behavior. A subsequent functional screening of neural circuitry by chemogenetic inhibition reveals the orbitofrontal cortex (OFC) as a candidate for this form of choice. Notably, we found that OFC plays a specific role in embedding the recurrent choice pattern into the fixed schema for action selection, but not in merely defining conflicting choice. Consistently, we uncover that OFC ablation leaves animals ability intact to make a conflicting choice, but selectively disrupts the formation of the fixed action schema. These findings suggest that OFC is crucial to ensure persistency in action selection by solidifying extensive history of recurrent choices into a firmly established schema of action selection, providing novel insights into how the stability and persistency of behavior are held in the brain.

neuroscience↗

bioRxiv2024

Mora-ERP-based RNN-Transformer for decoding single-trial EEGs during silent Japanese speeches

We developed a method for decoding single-trial electroencephalography (EEG) during silent Japanese speeches. In order to cope with problems that there would be always noises in single-trial EEGs, a recurrent neural network (RNN) was used which could reproduce signals under noises. Each of silent-mora-related potentials and the single-trial EEG minus the event-related potential (ERP) were assigned to the signal and the noise, respectively, with reference to the averaging principle. Next, in our Transformer, dot product between the RNN output and the single-trial EEG after positional encoding then Softmax with Loss yielded probabilities of moras, each of which consists of silent Japanese words, phrases or part of sentences. The present decoding was completed by tracing the maximal probability at each block representing time. Average mora error rates (MERs) on pretrained and validated performances for the patient was as low as 1.5 % and 0 %, respectively. The performance for the testing would be refined by many single-trial EEGs during silent Japanese speeches obtained by EEG Web interfaces. This method might be applied to other "mora" languages.

neuroscience↗

bioRxiv2024

E3 ligase Praja1 mediates ubiquitination and degradation of microtubule-associated protein Tau

RING-H2 type E3 ligase Praja family is composed of Praja1 and Praja2, which promote the degradation of substrates through the ubiquitin-proteasome system. Both paralogs contribute to neuronal maturation and differentiation, indicating a significant role in the nervous system. Aggregation-prone proteins associated with neurodegenerative diseases, including TDP-43 and -synuclein, are degraded and/or suppressed by Praja1. Furthermore, the expression level of the MAPT gene, which is frequently mutated in Alzheimers, is regulated by Praja2. While the Praja family has been shown to recognize various aggregation-prone proteins as substrates, it has not been determined whether Tau, a key protein that aggregates in tauopathies, is also recognized by Praja proteins. In this study, we show that Praja1, but not Praja2, recognizes Tau as a candidate substrate. We observed that Tau expression in human neuroblastoma SH-SY5Y cells decreased depending on the E3 ligase activity of Praja1. Furthermore, Praja1 polyubiquitinated and interacted with Tau, indicating that it is a target substrate. Next, by combining ancestral sequence reconstruction and mutational analysis, we revealed that the Praja1-Tau interaction began via deletion of the N- and C-terminal regions of Praja1, occurring just after the duplication of the Praja family in the common ancestor of placentals. Lastly, to test whether this interaction is disrupted under pathological conditions, P301L Tau was introduced, resulting in a degradation similar to that of wild-type Tau. These results reveal an unidentified mechanism of Tau proteostasis by Praja1 and may provide insight into the pathogenesis of neurodegenerative diseases, including tauopathy.

biochemistry↗

bioRxiv2023

Nationwide genome surveillance of carbapenem-resistant Pseudomonas aeruginosa in Japan

Japan is a country with an approximate 10 % prevalence rate of carbapenem-resistant Pseudomonas aeruginosa (CRPA). Currently, a comprehensive overview of the genotype and phenotype patterns of CRPA in Japan is lacking. Herein, we conducted genome sequencing and quantitative antimicrobial susceptibility testing for 382 meropenem-resistant CRPA isolates that were collected from 78 hospitals across Japan from 2019 to 2020. CRPA exhibited susceptibility rates of 52.9%, 26.4%, and 88.0% against piperacillin-tazobactam, ciprofloxacin, and amikacin, respectively, whereas 27.7% of CRPA isolates were classified as difficult-to-treat resistance P. aeruginosa. Of the 148 sequence types detected, ST274 (9.7%) was predominant, followed by ST235 (7.6%). The proportion of urine isolates in ST235 was higher than that in other STs (P = 0.0056, chi-square test). Only 4.1% of CRPA isolates carried the carbapenemase genes: blaGES (2) and blaIMP (13). One ST235 isolate carried the novel blaIMP variant blaIMP-98 in the chromosome. Regarding chromosomal mutations, 87.1% of CRPA isolates possessed inactivating or other resistance mutations in oprD, and 28.8% showed mutations in the regulatory genes (mexR, nalC, and nalD) for the MexAB-OprM effux pump. Additionally, 4.7% of CRPA isolates carried a resistance mutation in the PBP3-encoding gene ftsI. The findings from this study and other surveillance studies collectively demonstrate that CRPA exhibits marked genetic diversity and that its multidrug resistance in Japan is less prevailed than in other regions. This study contributes a valuable dataset that addresses a gap in genotype/phenotype information regarding CRPA in the Asia-Pacific region, where the epidemiological background markedly differs between regions.

microbiology↗

bioRxiv2023

Diurnal variation of brain activity in the human suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is the central clock for circadian rhythms. Animal studies have revealed daily rhythms in the neuronal activity in the SCN. However, the circadian activity of the human SCN has remained elusive. In this study, to reveal the diurnal variation of the SCN activity in humans, the SCN was localized, and its activity was investigated using perfusion imaging. We scanned each participant four times a day, every six hours, and higher activity was observed at noon while lower activity was recorded in the early morning. The SCN activity was then measured every thirty minutes for six hours from midnight to dawn and showed a decreasing trend and was comparable with the rodent SCN activity after switching off the lights. These results suggest that the diurnal variation of the human SCN follows the zeitgeber cycles of mammals and is modulated by physical lights rather than the local time.

neuroscience↗

bioRxiv2023

Scalable phylogenetic Gaussian process models improve the detectability of environmental signals on extinction risks for many Red List species

1. Conservation biologists have a daunting task of understanding the causes of species decline associated with anthropogenic factors and predicting the extinction risk of a growing number of endangered species. By stabilising estimates with information on closely related species, phylogenetic information among species can bridge gaps in information on species with small sample sizes when modelling large numbers of endangered species. However, modelling many species with the Gaussian process (GP), which underlies the evolutionary process of phylogenetic random effects, remains a challenge owing to the computational burden in estimating the large variance-covariance matrix. 2. Here, we applied a phylogenetic generalised mixed model with random slopes and random intercepts to 1,010 endangered vascular plant taxa in Japan following phylogenetic GPs implemented by nearest neighbour GP (NNGP) approximation. NNGP enables flexibility in changing the proximity on the phylogenetic tree of species from which information is borrowed to stabilise parameter estimates with a realistic computational burden. We evaluated the effectiveness of phylogenetic models by comparing the predictive performance and descriptive power of phylogenetic and non-phylogenetic models and identified the anthropogenic factors contributing to the decline of each of the studied endangered species. 3. We found that the model with phylogenetic information had better prediction performance than the model without phylogenetic information. The results showed that across all explanatory variables, the phylogenetic model could detect interspecific differences in response to environmental factors in a number of species more clearly. Combined with the phylogenetic signal results, we could also detect a phylogenetic bias in the species that could benefit from the positive effects of protected areas but reduce the extinction risk of 95% of all studied taxa. 4. In conclusion, our model, considering phylogenetic information with NNGP, allows the elucidation of factors causing the decline of many endangered species. In future analyses, the estimation of extinction probability linked to environmental change using such modelling might be applied to future climate-land use scenarios, advancing the comprehensive assessment of biodiversity degradation and threats to species at multiple scales.

ecology↗

bioRxiv2023

Reprogramming Intrahepatic Cholangiocarcinoma Immune Microenvironment by Chemotherapy and CTLA-4 Blockade Enhances Anti-PD1 Therapy

Intrahepatic cholangiocarcinoma (ICC) has limited therapeutic options and a dismal prognosis. Anti-PD-L1 immunotherapy combined with gemcitabine/cisplatin chemotherapy has recently shown efficacy in biliary tract cancers, but responses are seen only in a minority of patients. Here, we studied the roles of anti-PD1 and anti-CTLA-4 immune checkpoint blockade (ICB) therapies when combined with gemcitabine/cisplatin and the mechanisms of treatment benefit in orthotopic murine ICC models. We evaluated the effects of the combined treatments on ICC vasculature and immune microenvironment using flow cytometry analysis, immunofluorescence, imaging mass cytometry, RNA-sequencing, qPCR, and in vivo T-cell depletion and CD8+ T-cell transfer using orthotopic ICC models and transgenic mice. Combining gemcitabine/cisplatin with anti-PD1 and anti-CTLA-4 antibodies led to substantial survival benefits and reduction of morbidity in two aggressive ICC models, which were ICB-resistant. Gemcitabine/cisplatin treatment increased the frequency of tumor-infiltrating lymphocytes and normalized the ICC vessels, and when combined with dual CTLA-4/PD1 blockade, increased the number of activated CD8+Cxcr3+IFN-{gamma}+ T-cells. Depletion of CD8+ but not CD4+ T-cells compromised efficacy. Conversely, CD8+ T-cell transfer from Cxcr3-/- versus Cxcr3+/+ mice into Rag1-/- immunodeficient mice restored the anti-tumor effect of gemcitabine/cisplatin/ICB combination therapy. Finally, rational scheduling of the ICBs (anti-CTLA-4 "priming") with chemotherapy and anti-PD1 therapy achieved equivalent efficacy with continuous dosing while reducing overall drug exposure. In summary, gemcitabine/cisplatin chemotherapy normalizes vessel structure, increases activated T-cell infiltration, and enhances anti-PD1/CTLA-4 immunotherapy efficacy in aggressive murine ICC. This combination approach should be clinically tested to overcome resistance to current therapies in ICC patients. One Sentence SummaryImmune microenvironment reprogramming by chemotherapy and priming using CTLA-4 blockade render ICCs responsive to anti-PD-1 immunotherapy.

cancer biology↗

bioRxiv2022

Characterization of HcaA, a novel autotransporter protein in Helicobacter cinaedi, and its role in host cell adhesion

Helicobacter cinaedi infects the human gut and causes invasive infections such as bacteremia and cellulitis through bacterial translocation. However, the mechanism by which H. cinaedi attaches to host cells and establishes infection remains unclear. This study aimed to investigate the relationship between a novel putative autotransporter protein, H. cinaedi autotransporter protein A (HcaA), and its role in pathogenicity. The cytotoxicity of H. cinaedi infection in colon epithelial cell lines (Caco-2 and HT-29) was assessed using a lactate dehydrogenase assay, and it was found that cytotoxicity significantly decreased upon HcaA knockout. Adhesion assays further revealed that the HcaA-knockout strain showed significantly reduced attachment to the human epithelial colorectal adenocarcinoma cell line (Caco-2) compared to that of the wild-type strain. Moreover, the recombinant HcaA protein demonstrated strong adhesion properties to the human monocytic cell line (U937). The adhesive activity was diminished when the RGD motif in HcaA was replaced with RAD, indicating that the RGD motif in HcaA is crucial for host cell adhesion. To determine the role of HcaA in H. cinaedi infection in vivo, C57BL/6 mice were orally infected with wild-type and HcaA-knockout H. cinaedi strains. Bacterial colonization was assessed 7, 14, and 28 days post-infection. At 7 days post-infection, colonization was significantly lower in mice infected with the HcaA-knockout strain compared to those infected with the wild-type strain. In conclusion, our findings suggest that HcaA, a novel putative autotransporter protein in H. cinaedi, plays a significant role as an adhesin in establishing colonization. IMPORTANCEHelicobacter species are classified as gastric or enterohepatic according to their habitat. Among enterohepatic Helicobacter species, which inhabit the intestine, colon and liver, H. cinaedi has been most frequently isolated from humans. H. cinaedi often causes bacteremia and cellulitis in immunocompromised hosts. Here, we focused on the H. cinaedi autotransporter protein A (HcaA), a novel virulence factor in H. cinaedi. We discovered that HcaA contributes to cell adhesion via its RGD motif. Furthermore, in animal experiments, bacterial colonization was reduced in mice infected with HcaA-knockout strains, supporting the hypothesis that HcaA contributes to H. cinaedi adhesion to host cells. Our study provides a novel mechanism for the establishment of H. cinaedi infections and provides new insights into the role of autotransporter proteins in the establishment of Helicobacter infection.

microbiology↗

bioRxiv2022

A fungal secondary metabolism gene cluster enables mutualist-pathogen transition in root endophyte Colletotrichum tofieldiae

Plant-associated fungi show diverse lifestyles from pathogenic to mutualistic to the host; however, the principles and mechanisms through which they shift the lifestyles require elucidation. The root fungus Colletotrichum tofieldiae (Ct) promotes Arabidopsis thaliana growth under phosphate limiting conditions. We reveal a Ct strain, designated Ct3, that severely inhibits plant growth. Ct3 pathogenesis occurs through activation of host abscisic acid (ABA) pathways via a fungal secondary metabolism gene cluster related to sesquiterpene ABA and botrydial (BOT) biosynthesis. ABA-BOT cluster activation during root infection suppresses host nutrient uptake-related genes and changes the mineral contents, suggesting its role in manipulating host nutrition states. Conversely, disruption or environmental suppression of the cluster renders Ct3 beneficial for plant growth, in a manner dependent on host phosphate starvation response regulators. Our findings indicate that a fungal metabolism cluster provides a means by which infectious fungi modulate lifestyles along the parasitic-mutualistic continuum in fluctuating environments.

microbiology↗

bioRxiv2022

IFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation

Activating mutations of KRAS play critical roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence indicates that distinct KRAS alleles associate with different prognoses, but the underlying mechanisms are not known. We established isogenic KRAS mutants (KRASG12D, KRASG12V, and KRASWT) using a KRASG12R patient-derived PDAC cell line by CRISPR/Cas9 knock-in. We used these isogenic cell lines, a collection of characterized human PDAC patient-derived cell lines, and murine PDAC models to study the role of these KRAS alleles in vitro and in vivo. We verified that the growth of KRASG12D cells is more aggressive compared to KRASG12V isogenic cells in vitro and in vivo using orthotopic mouse models. Signal transducer and activator of transcription (STAT) activation was the most significant difference between KRASG12D and KRASG12V isogenic PDACs. Furthermore, activation of interferon-alpha (IFNA)/IFNA receptor (IFNAR)1/STAT3 signaling in the cancer cells mediated the more aggressive phenotype of KRASG12D PDACs. Conversely, inhibition of IFNAR1 in patient-derived PDAC cells suppressed tumor growth. Finally, IFNAR1 blockade was also effective in murine PDAC models and induced a significant increase in survival when combined with immune checkpoint blockade therapy. We conclude that the IFNA pathway and IFNAR1/STAT3 axis contribute to a more aggressive tumor progression in human KRASG12D PDACs and that IFNAR1 inhibition is a potential therapeutic target for overcoming resistance to immunotherapy in PDAC. One Sentence SummaryIFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation.

cancer biology↗

bioRxiv2021

Defensive nymphs in the water-repellent gall of the social aphid Colophina monstrifica (Hemiptera: Aphididae: Eriosomatinae)

The aphid Colophina monstrifica forms woolly colonies with sterile soldiers on the secondary host Clematis uncinata in Taiwan. However, the gall or primary-host generation of C. monstrifica has not been found to date. We successfully induced galls of the species on trees of Zelkova serrata through attaching its eggs onto the trees, and also found a few naturally formed galls on another Z. serrata tree. The identity of the aphids was confirmed by examining their morphology and mitochondrial DNA sequences. First- and second-instar nymphs in the galls exhibited attacking behavior toward artificially introduced moth larvae. Observations with a scanning electron microscope revealed that the gall inner surface was densely covered with minute trichomes. This indicates the water repellency of the inner surface, and strongly suggests that young nymphs of C. monstrifica dispose of honeydew globules outside the gall, as known in the congener C. clematis.

zoology↗

bioRxiv2020

Anti-severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) potency of Mefloquine as an entry inhibitor in vitro

Coronavirus disease 2019 (COVID-19) has caused serious public health, social, and economic damage worldwide and effective drugs that prevent or cure COVID-19 are urgently needed. Approved drugs including Hydroxychloroquine, Remdesivir or Interferon were reported to inhibit the infection or propagation of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), however, their clinical efficacies have not yet been well demonstrated. To identify drugs with higher antiviral potency, we screened approved anti-parasitic/anti-protozoal drugs and identified an anti-malarial drug, Mefloquine, which showed the highest anti-SARS-CoV-2 activity among the tested compounds. Mefloquine showed higher anti-SARS-CoV-2 activity than Hydroxychloroquine in VeroE6/TMPRSS2 and Calu-3 cells, with IC50 = 1.28 M, IC90 = 2.31 M, and IC99 = 4.39 M in VeroE6/TMPRSS2 cells. Mefloquine inhibited viral entry after viral attachment to the target cell. Combined treatment with Mefloquine and Nelfinavir, a replication inhibitor, showed synergistic antiviral activity. Our mathematical modeling based on the drug concentration in the lung predicted that Mefloquine administration at a standard treatment dosage could decline viral dynamics in patients, reduce cumulative viral load to 7% and shorten the time until virus elimination by 6.1 days. These data cumulatively underscore Mefloquine as an anti-SARS-CoV-2 entry inhibitor.

microbiology↗

bioRxiv2020

Multidrug treatment with nelfinavir and cepharanthine against COVID-19

Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) are urgently required. We screened a panel of already-approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.

microbiology↗