Gut bacteria alleviate smoking-related NASH by degrading gut nicotine.

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD)1-5, but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression.

Bay41-4109-induced aberrant polymers of hepatitis b capsid proteins are removed via STUB1-promoted p62-mediated macroautophagy.

The hepatitis B virus (HBV) core protein (HBc) functions in multiple steps of the viral life cycle. Heteroaryldihydropyrimidine compounds (HAPs) such as Bay41-4109 are capsid protein allosteric modulators that accelerate HBc degradation and inhibit the virion secretion of HBV, specifically by misleading HBc assembly into aberrant non-capsid polymers. However, the subsequent cellular fates of these HAP-induced aberrant non-capsid polymers are not well understood. Here, we discovered that that the chaperone-binding E3 ubiquitin ligase protein STUB1 is required for the removal of Bay41-4109-induced aberrant non-capsid polymers from HepAD38 cells. Specifically, STUB1 recruits BAG3 to transport Bay41-4109-induced aberrant non-capsid polymers to the perinuclear region of cells, thereby initiating p62-mediated macroautophagy and lysosomal degradation. We also demonstrate that elevating the STUB1 level enhances the inhibitory effect of Bay41-4109 on the production of HBeAg and HBV virions in HepAD38 cells, in HBV-infected HepG2-NTCP cells, and in HBV transgenic mice. STUB1 overexpression also facilitates the inhibition of Bay41-4109 on the cccDNA formation in de novo infection of HBV. Understanding these molecular details paves the way for applying HAPs as a potentially curative regimen (or a component of a combination treatment) for eradicating HBV from hepatocytes of chronic infection patients.

Reduction of WDR81 impairs autophagic clearance of aggregated proteins and cell viability in neurodegenerative phenotypes.

Neurodegenerative diseases are characterized by neuron loss and accumulation of undegraded protein aggregates. These phenotypes are partially due to defective protein degradation in neuronal cells. Autophagic clearance of aggregated proteins is critical to protein quality control, but the underlying mechanisms are still poorly understood. Here we report the essential role of WDR81 in autophagic clearance of protein aggregates in models of Huntington's disease (HD), Parkinson's disease (PD) and Alzheimer's disease (AD). In hippocampus and cortex of patients with HD, PD and AD, protein level of endogenous WDR81 is decreased but autophagic receptor p62 accumulates significantly. WDR81 facilitates the recruitment of autophagic proteins onto Htt polyQ aggregates and promotes autophagic clearance of Htt polyQ subsequently. The BEACH and MFS domains of WDR81 are sufficient for its recruitment onto Htt polyQ aggregates, and its WD40 repeats are essential for WDR81 interaction with covalent bound ATG5-ATG12. Reduction of WDR81 impairs the viability of mouse primary neurons, while overexpression of WDR81 restores the viability of fibroblasts from HD patients. Notably, in Caenorhabditis elegans, deletion of the WDR81 homolog (SORF-2) causes accumulation of p62 bodies and exacerbates neuron loss induced by overexpressed α-synuclein. As expected, overexpression of SORF-2 or human WDR81 restores neuron viability in worms. These results demonstrate that WDR81 has crucial evolutionarily conserved roles in autophagic clearance of protein aggregates and maintenance of cell viability under pathological conditions, and its reduction provides mechanistic insights into the pathogenesis of HD, PD, AD and brain disorders related to WDR81 mutations.

TFEB acetylation promotes lysosome biogenesis and ameliorates Alzheimer's disease-relevant phenotypes in mice.

Lysosomes are one of the major centers for regulating cargo degradation and protein quality control. Transcription factor EB (TFEB)-promoted lysosome biogenesis enhances lysosome-mediated degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB modification and activation are still poorly understood. Here, we report essential roles of TFEB acetylation in TFEB nuclear translocation and lysosome biogenesis, which are independent of TFEB dephosphorylation. By screening small molecules, we find that Trichostatin A (TSA), the pan-inhibitor of histone deacetylases (HDACs), promotes nuclear translocation of TFEB. TSA enhances the staining of cells by LysoTracker Red and increases the expression of lysosomal and autophagic genes. We identify four novel acetylated lysine residues in TFEB, which are important for TFEB nuclear translocation and lysosome biogenesis. We show that TFEB acetylation is regulated by HDACs (HDAC5, HDAC6, and HDAC9) and lysine acetyltransferases (KATs), including ELP3, CREBBP, and HAT1. During TSA-induced cytosol-to-nucleus translocation of TFEB, acetylation is independent of TFEB dephosphorylation, since the mTORC1- or GSK3ß-related phosphorylation sites on TFEB are still phosphorylated. Administration of TSA to APP/PS1 mice increases the expression of lysosomal and autophagic genes in mouse brains and also improves memory. Accordingly, the ß-amyloid plaque burden is decreased. These results show that the acetylation of TFEB, as a novel mechanism of TFEB activation, promotes lysosome biogenesis and alleviates the pathogenesis of Alzheimer's disease. Our results also suggest that HDAC inhibition can promote lysosome biogenesis, and this may be a potential therapeutic approach for the treatment of neurodegenerative diseases and disorders related to HDAC hyperactivation.

Inhibition of the dopamine transporter promotes lysosome biogenesis and ameliorates Alzheimer's disease-like symptoms in mice.

INTRODUCTION: Lysosomes are degradative organelles that maintain cellular homeostasis and protein quality control. Transcription factor EB (TFEB)-mediated lysosome biogenesis enhances lysosome-dependent degradation and alleviates neurodegenerative diseases, but the mechanisms underlying TFEB regulation and modification are still poorly understood. METHODS: By screening novel small-molecule compounds, we identified a group of lysosome-enhancing compounds (LYECs) that promote TFEB activation and lysosome biogenesis. RESULTS: One of these compounds, LH2-051, significantly inhibited the function of the dopamine transporter (DAT) and subsequently promoted lysosome biogenesis. We uncovered cyclin-dependent kinase 9 (CDK9) as a novel regulator of DAT-mediated lysosome biogenesis and identified six novel CDK9-phosphorylated sites on TFEB. We observed that signal transduction by the DAT-CDK9-TFEB axis occurs on lysosomes. Finally, we found that LH2-051 enhanced the degradation of amyloid beta plaques and improved the memory of amyloid precursor protein (APP)/Presenilin 1 (PS1) mice. DISCUSSION: We identified the DAT-CDK9-TFEB signaling axis as a novel regulator of lysosome biogenesis. Our study sheds light on the mechanisms of protein quality control under pathophysiological conditions.

Formosanin C attenuates lipopolysaccharide-induced inflammation through nuclear factor-κB inhibition in macrophages.

Extended inflammation and cytokine production pathogenically contribute to a number of inflammatory disorders. Formosanin C (FC) is the major diosgenin saponin found in herb Paris formosana Hayata (Liliaceae), which has been shown to exert anti-cancer and immunomodulatory functions. In this study, we aimed to investigate anti-inflammatory activity of FC and the underlying molecular mechanism. RAW264.7 macrophages were stimulated with lipopolysaccharide (LPS) or pretreated with FC prior to being stimulated with LPS. Thereafter, the macrophages were subjected to analysis of the expression levels of pro-inflammatory mediators, including nitric oxide (NO), prostaglandin E2 (PGE), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and IL-6, as well as two relevant enzymes, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). The analysis revealed that FC administration blunted LPS-induced production of NO and PGE in a dose-dependent manner, while the expression of iNOS and COX-2 at both mRNA and protein levels was inhibited in LPS-stimulated macrophages pre-treated with FC. Moreover, LPS stimulation upregulated mRNA expression and medium release of TNF-α, IL-1ß, and IL- 6, whereas this effect was blocked upon FC pre-administration. Mechanistic studies showed that inhibitory effects of FC on LPS-induced inflammation were associated with a downregulation of IκB kinase, IκB, and p65/NF-κB pathway. Taken together, these data suggest that FC possesses an inflammation-suppressing activity, thus being a potential agent for the treatment of inflammation-associated disorders.

Syntheses, antiviral activities and induced resistance mechanisms of novel quinazoline derivatives containing a dithioacetal moiety.

A series of novel quinazoline derivatives containing a dithioacetal moiety were designed and synthesized, and their structures were characterized by 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and high-resolution mass spectrometry. Bioassay results indicated that compound 4b exhibited remarkable protective activity against cucumber mosaic virus (CMV, EC50 = 248.6 µg/mL) and curative activity against potato virus Y (EC50 = 350.5 µg/mL), which were better than those of ningnanmycin (357.7 µg/mL and 493.7 µg/mL, respectively). Moreover, compound 4b could increase the chlorophyll content in plants, improve photosynthesis, and effectively induce tobacco anti-CMV activity.

Induced Resistance Mechanism of Novel Curcumin Analogs Bearing a Quinazoline Moiety to Plant Virus.

Plant immune activators can protect crops from plant virus pathogens by activating intrinsic immune mechanisms in plants and are widely used in agricultural production. In our previous work, we found that curcumin analogs exhibit excellent biological activity against plant viruses, especially protective activity. Inspired by these results, the active substructure of pentadienone and quinazoline were spliced to obtain curcumin analogs as potential exogenously induced resistant molecule. Bioassay results showed that compound A13 exhibited excellent protective activity for tobacco to against Tobacco mosaic virus (TMV) at 500 µg/mL, with a value of 70.4 ± 2.6% compared with control treatments, which was better than that of the plant immune activator chitosan oligosaccharide (49.0 ± 5.9%). The protective activity is due to compound A13 inducing tobacco resistance to TMV, which was related to defense-related enzymes, defense-related genes, and photosynthesis. This was confirmed by the up-regulated expression of proteins that mediate stress responses and oxidative phosphorylation.

Novel α,ß-unsaturated amide derivatives bearing α-amino phosphonate moiety as potential antiviral agents.

Based on flexible construction and broad bioactivity of ferulic acid, a series of novel α,ß-unsaturated amide derivatives bearing α-aminophosphonate moiety were designed, synthesized and systematically evaluated for their antiviral activity. Bioassay results indicated that some compounds exhibited good antiviral activities against cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) in vivo. Especially, compound g18 showed excellent curative and protective activities against CMV, with half-maximal effective concentration (EC50) values of 284.67µg/mL and 216.30µg/mL, which were obviously superior to that of Ningnanmycin (352.08µg/mL and 262.53µg/mL). Preliminary structure-activity relationships (SARs) analysis revealed that the introduction of electron-withdrawing group at the 2-position or 4-position of the aromatic ring is favorable for antiviral activity. Present work provides a promising template for development of potential inhibitor of plant virus.

Synthesis, antiviral activity, and molecular docking study of trans-ferulic acid derivatives containing acylhydrazone moiety.

In this study, we report the synthesis and antiviral activity of trans-ferulic acid derivatives containing acylhydrazone moiety. Biological tests demonstrated that most target compounds showed potent antiviral activity against tobacco mosaic virus (TMV). Compound D4 showed remarkable inactivating activity with EC50 value of 36.59µg/mL, which was obviously superior to ribavirin (126.05µg/mL). Molecular docking results revealed that compound D4 exhibited the optimal combining capacity with five hydrogen bonds to different amino-acid residues of TMV coat protein (TMV-CP). Docking results were consistent with the inactivating activity of target compounds against TMV.

[The Effect in Extraction of Different Ratio of Dahuang-Taoren for Ten Kinds of Chemical Constituents from Rhizoma Rhei].

Objective: To investigate the effect of Dahuang-Taoren with different proportion of extraction amount changes of ten kinds of chemical constituents in Rhizoma Rhei. Methods: Uniform method to set different ratio( 1∶ 5,2∶ 5,2∶ 3,1∶ 1,3∶ 2,5∶ 2,5∶ 1),and set the control group ( Dahuang-Taoren( 1 ∶ 0). HPLC was used to determine the content of ten constituents as gallic acid,( +)-catechin,sennoside B,anthraquinones( aloe-emodin,rhein,emodin,chrysophanol,physcion,chrysophanol-1-O-glucoside,emodin major grape glycoside) in different ratio of drug. Different proportions of Dahuang-Taoren on the extraction amount of ten chemical components in Rhizoma Rhei changes were analyzed. . Results: Compared to the control group, Dahuang-Taoren with different ratio( 5∶ 1,5∶ 2,3∶ 2) in a sample with increasing proportion of Taoren,the extraction amount of ten kinds of constituents of Rhizoma Rhei gradually decreased;Dahuang-Taoren with ratio of 1∶ 1,ten kinds of constituents in extraction of total amount arrived minimum value. Dahuang-Taoren with different ratio( 2∶ 3,2∶ 5,1∶ 5) in a sample with increasing proportion of Taoren,the extraction amount of gallic acid,( +) catechin,chrysophanol of Rhizoma Rhei increased significantly. Conclusion: There is obvious change in chemical constituents of the extraction amount of Rhizoma Rhei with the change of the ratio in Dahuang-Taoren, and Dahuang-Taoren with the ratio( 2∶ 3,2∶ 5,1∶ 5),the extraction amount of gallic acid,( +)-catechin,sennoside B,aloe-emodin,emodin,chrysophanol,physcion,chrysophanol-1-O-glucoside are significantly higher than control group.

Risk factors for intraprocedural hypoxemia in patients with acute cerebral ischemia treated with vascular intervention and its impact on prognosis: A retrospective cohort study.

BACKGROUND: Acute cerebral infarction (ACI) is one of the most common ischemic cerebrovascular diseases in neurology, with high morbidity, mortality, and disability. Early thrombolytic treatment of ACI has significant efficacy, but intraprocedural complications of hypoxemia can significantly reduce the efficacy. This study aims to analyze the risk factors for intraprocedural hypoxemia in patients with ACI, so as to take effective measures in advance to reduce the likelihood of adverse patient outcomes. METHODS: We retrospectively analyzed a total of 238 patients with ACI treated with vascular interventions from May 2017 to May 2022. To assess and collate the patients' characteristics, factors associated with the development of intraprocedural hypoxemia. The independent risk factors for the development of intraprocedural hypoxemia were analyzed by binary logistic regression. RESULTS: A total of 238 patients were included in this study. Of these, intraprocedural hypoxemia occurred in 89 (37.4%). The results showed that old age (odds ratio [OR] = 2.666, P = 0.009), obesity (OR = 3.029, P = 0.003), smoking history (OR = 2.655, P = 0.010), preoperative oxygen saturation (SpO2) (OR = 0.001, P = 0.042), preoperative C-reactive protein (OR = 1.216, P = 0.002), and time from puncture to vascular recanalization (OR = 1.135, P = 0.000) were independent risk factors for intraprocedural hypoxemia in patients. The prognosis of the patients was assessed according to the modified Rankin scale, and the prognosis of the nonhypoxemia group was significantly better than that of the hypoxemia group. Regression analysis showed that intraprocedural hypoxemia (OR = 0.360, P = 0.001), postoperative lower extremity vein thrombosis (OR = 0.187, P = 0.018), hydrocephalus (OR = 0.069, P = 0.015), intracranial hemorrhage (OR = 0.116, P = 0.002), and reocclusion (OR = 0.217, P = 0.036) were independent risk factors for poor prognosis. CONCLUSIONS: Currently, intravascular hypoxemia in patients with ACI has a serious impact on prognosis. Clinical work should attach great importance to the clinical characteristics of patients, identify relevant risk factors, and aggressively take personalized therapeutic actions to improve patients' prognosis.

Obstructive Sleep Apnea Syndrome Exacerbates NASH Progression via Selective Autophagy-Mediated Eepd1 Degradation.

Obstructive sleep apnea syndrome (OSAS), characterized by chronic intermittent hypoxia (CIH), is an independent risk factor for aggravating non-alcoholic steatohepatitis (NASH). The prevailing mouse model employed in CIH research is inadequate for the comprehensive exploration of the impact of CIH on NASH development due to reduced food intake observed in CIH-exposed mice, which deviates from human responses. To address this issue, a pair-feeding investigation with CIH-exposed and normoxia-exposed mice is conducted. It is revealed that CIH exposure aggravates DNA damage, leading to hepatic fibrosis and inflammation. The analysis of genome-wide association study (GWAS) data also discloses the association between Eepd1, a DNA repair enzyme, and OSAS. Furthermore, it is revealed that CIH triggered selective autophagy, leading to the autophagic degradation of Eepd1, thereby exacerbating DNA damage in hepatocytes. Notably, Eepd1 liver-specific knockout mice exhibit aggravated hepatic DNA damage and further progression of NASH. To identify a therapeutic approach for CIH-induced NASH, a drug screening is conducted and it is found that Retigabine dihydrochloride suppresses CIH-mediated Eepd1 degradation, leading to alleviated DNA damage in hepatocytes. These findings imply that targeting CIH-mediated Eepd1 degradation can be an adjunctive approach in the treatment of NASH exacerbated by OSAS.

LYECs: lysosome-enhancing compounds as potential therapeutic approaches for Alzheimer disease.

More than 55 million people are suffering from Alzheimer's disease (AD), but there is still no effective treatment for it. Therefore, novel therapeutic approaches and regulatory mechanisms of protein quality control need to be further evaluated and dissected. The lysosome is one of the major degradative organelles that maintain cellular homeostasis and protein quality control. In our recent study, we have identified a group of LYsosome-Enhancing Compounds (LYECs), which significantly promote the activation of TFEB (transcription factor EB) and lysosome biogenesis via inhibiting dopamine transporters (DAT). Injection of LH2-051, a member of the LYECs identified in this study, significantly improves learning, memory, and cognitive function of APP-PSEN1 mice, in which the enhanced capability of lysosomal degradation promotes the clearance of amyloid protein aggregates. In summary, this study reports novel mechanisms of neurotransporter-mediated lysosome biogenesis and shows that DAT inhibition can alleviate the pathogenesis of Alzheimer's disease.

Inactivating Activities and Mechanism of Imidazo[1,2-c]pyrimidin-5(6H)-one Nucleoside Derivatives Incorporating a Sulfonamide Scaffold.

Twenty-eight imidazo[1,2-c]pyrimidin-5(6H)-one nucleoside derivatives incorporating a sulfonamide scaffold with preferable inactivating activities on pepper mild mottle virus (PMMoV) were designed and synthesized. Then, compound B29 with illustrious inactivating activity against PMMoV was received on the basis of the three-dimensional quantitative structure-activity relationship (3D-QSAR) model, with the EC50 of 11.4 µg/mL, which was superior to ningnanmycin (65.8 µg/mL) and template molecule B16 (15.3 µg/mL). Furthermore, (1) transmission electron microscopy (TEM) indicated that B29 could cause severe fracture of virions; (2) microscale thermophoresis (MST) and molecular docking further demonstrated that B29 had faintish binding affinities with PMMoV CPR62A (Kd = 202.84 µM), PMMoV CPL144A (Kd = 141.57 µM), and PMMoV CPR62A,L144A (Kd = 332.06 µM) compared to PMMoV CP (Kd = 4.76 µM); and (3) western blot and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) results of pCB-GFP-PMMoV CPR62A, pCB-GFP-PMMoV CPL144A, and pCB-GFP-PMMoV CPR62A,L144A were consistent with MST and confocal. In brief, the above results indicated that the amino acids at positions 62 and 144 of PMMoV CP might be the key amino acid sites of B29 acted on.

Development and Mechanism Investigation of Novel Thioacetalized Indoles as Antiphytoviral Agents.

Potato virus Y (PVY) is a highly destructive pathogen that infects Solanum tuberosumvL., commonly known as potato, a crop that produces one of the most crucial food staples of the world. The PVY viral infection can considerably reduce the yield and quality of potatoes, thereby causing significant economic ramifications. Given the unsatisfactory performance of commercially available antiviral agents against PVY, we synthesized a series of novel indole-derived compounds followed by their bioevaluation and investigation of the mechanisms governing their anti-PVY activity. These indole-based derivatives contain dithioacetal as a key chemical moiety, and most of them exhibit promising anti-PVY activities. In particular, compound B2 displays remarkable in vivo protective and inactivating properties, with half-maximal effective concentration (EC50) values of 209.3 and 113.0 µg/mL, respectively, in stark contrast to commercial agents such as ningnanmycin (EC50 = 281.4 and 136.3 µg/mL, respectively) and ribavirin (EC50 = 744.8 and 655.4 µg/mL, respectively). The mechanism using which B2 enhances plant immune response to protect plants from PVY is elucidated using enzyme activity tests, real-time quantitative polymerase chain reaction (RT-qPCR), and proteomics techniques. This study aims to pave the way for developing candidate pesticides and related molecules using antiphytoviral activity.

Bark-stripping Behavior of Formosan Sambar (Rusa unicolor swinhoii) at Tataka, Yushan National Park in Taiwan.

The bark-stripping behavior of Formosan sambar, Rusa unicolor swinhoii, has become conspicuous in recent years in the Tataka area of Yushan National Park in Taiwan and a cause for concern to visitors and ecologists. We conducted a monthly survey of 537 tagged trees of 21 species and monitored the abundance of sambar using camera traps from October 2018 to January 2021, aiming to interpret possible causes of the bark-stripping behavior in Tataka. We also used a generalized linear model to evaluate factors that may affect the probability of a tree having its bark stripped. Both our observations and the model predictions showed that sambar has a strong preference for bark of Pinus armandii, Photinia niitakayamensis, and Salix fulvopubeseens and for trees with diameter at breast height around 14 cm. Bark stripping mainly occurred between July and October when major forage was most abundant. However, sambar's need for bark surged in May when sambar abundance was moderate and decreased in October when sambar abundance was high. The seasonality of bark stripping was synchronized with the peak periods of antler development, fawn nursing, and spread of gastrointestinal parasites, suggesting that sambar strips bark to ingest minerals for their physiological needs and/or to acquire plant secondary metabolites to repel gastrointestinal parasites. Sambar abundance alone was not sufficient to predict the overall intensity of bark stripping. Rather, the product of sambar abundance and the necessity index (average wound size) were strongly correlated with the overall bark-stripping intensity. Therefore, controlling sambar abundance is essential but it alone may not be the optimal strategy for controlling bark stripping. A combination of population control and relaxing of sambar's parasite loading and/or physiological needs for minerals is an important strategy to control the overall bark stripping. Future research could use the necessity index to investigate the synchronicity of the bark-stripping behavior, deer's physiological state, environmental factors and phenology to better understand the cause of this behavior.

Study on the Correlation Factors of Tumour Prognosis after Intravascular Interventional Therapy.

Noninvasive or minimally invasive interventional surgery was selected, and the complications were less and had no significant impact on the quality of life of patients. Tumour patients are often accompanied by cerebrovascular diseases, metabolic diseases, and other basic diseases, which more or less adversely affect the surgical efficacy of tumour. In this paper, endovascular remobilization was used to treat tumour; the basic condition of patients before operation and the interventional operation plan were introduced. Through the analysis of clinical data and prognosis evaluation results of tumour patients receiving intravascular interventional therapy, the patients were divided into good prognosis group and poor prognosis group according to the modified Rankin scale score at discharge. The relationship between gender, age, history of hypertension, tumour width, tumour size, preoperative Hunt-Hess grade, interventional surgery method, and prognosis related to intravascular interventional therapy was explored. The results showed that intravascular interventional therapy for tumour patients can obtain a good prognosis, which provides a reference for the future preoperative assessment of treatment risk and possible prognosis and provides a theoretical basis for the formulation of treatment plan to improve prognosis.

Design, Synthesis, Antiviral Bioactivity, and Mechanism of the Ferulic Acid Ester-Containing Sulfonamide Moiety.

Tobacco mosaic virus (TMV) has caused huge economic losses to tobacco, pepper, cucumber, and ornamental crops all over the world. However, few effective antiviral agents were developed and applied to control such plant disease. It is challenging to find an anti-TMV agent which is highly effective, less toxic, and environmentally friendly. In this work, a series of ferulic acid ester-containing sulfonamide moieties were designed and synthesized, and the antiviral activities of these compounds against TMV were evaluated. The anti-TMV biological activity test showed that the target compounds showed excellent anti-TMV activity in vitro and in vivo. In particular, compound 2 has excellent anti-TMV activity at 500 µg/mL, which is higher than that of the control drug ribavirin. The preliminary mechanism research results showed that compound 2 can obviously destroy the morphology of the virions to show excellent activity. The results show that the ferulic acid ester-containing sulfonamide moiety deserves further research and development.