Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production

Ren, Fang; Yang, Xiao; Hu, Zhong-Wen; Xu, Hongyan; Ren, Ji-Hua; Zhong, Shan; Jia, Xiaojiong; Jiang, Hui; Hu, Jieli; Cai, Xue-Fei; Zhang, Wenlu; Yao, Fang-Long; Yu, Haibo; Cheng, Sheng-Tao; Zhou, Hong-Zhong; Huang, Aiping; Law, Betty Yuen Kwan; Chen, Juan

doi:10.1016/j.ebiom.2019.10.022

Cited by 18 publications

(13 citation statements)

References 48 publications

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“…In terms of antivirus effect, NA has been reported to inhibit HIV infection at a post-integration step of the viral life cycle [31]. When testing an analogue of NA, 6-amino-nicotinamide (6-AN), signi cant antiviral effect towards hepatitis B virus (HBV) through inhibition of cccDNA transcription to achieve the anti-HBV effect were seen [32]. These are consistent with our nding that NA also potently suppressed rotavirus replication.…”

Section: Discussionsupporting

confidence: 80%

An Emerging Application of Cholesterol-lowering Therapy in Inhibition of Rotavirus Infection

Ding

Vuuren

2021

Preprint

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Despite the huge impact of rotavirus infection on global public health, there is no normally available drug against the virus worldwide. We have revealed the interaction of cholesterol metabolism and rotavirus replication, as well as identified statin as a promising drug to repress rotavirus infection, but the medical resources are greatly different across countries, so more drugs are needed for anti-rotavirus treatment in clinical activity. Two cell lines and a human small intestinal organoids were used as the models, which were infected by rotavirus SA11 strain. A clinically derived rotavirus virion, 026K strain, was measured intracellular virus RNA copies in Caco2 cells. We investigated the effects of different cholesterol-lowering drugs, including bisphosphonates (zoledronic acid, ZA), fibrate class (fenofibric acid, FA), vitamin B3 (nicotinic acid, NA), and ezetimibe on rotavirus replication in the pre-clinical models. All these cholesterol-lowering drugs resulted in significant decreases of rotavirus replication. The combinations of FA / ezetimibe with the statins had not the obvious synergies in the inhibition of rotavirus replication than any of them alone. Compared to the other drugs, ezetimibe showed the additional preventive and interference effects towards rotavirus infection. We describe an emerging application of clinical cholesterol-lowering therapy for anti-rotavirus treatment. These results could be directly considered when physicians treat with rotavirus-caused diseases worldwide.

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Section: Discussionsupporting

confidence: 80%

An Emerging Application of Cholesterol-lowering Therapy in Inhibition of Rotavirus Infection

Ding

Vuuren

2021

Preprint

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“…Studies have confirmed antimycobacterial effect of NAM in patients infected with Mycobacterium tuberculosis [ 121 , 122 ], while immune-mediated elimination was reported for Staphylococcus aureus , including MRSA and other major human pathogens such as Klebsiella pneumoniae and Pseudomonas aeruginosa [ 123 ]. In addition, NAM and its analogues exhibited antiviral effect in patients with HIV [ 121 ] and hepatitis B [ 124 ]. The potential treatment with NAD + intermediates has been recognized recently for combating COVID-19 infection that currently lacks efficient therapeutic or preventive agents and represents a global concern for public health.…”

Section: Infection Treatment and Immunomodulatory Effectsmentioning

confidence: 99%

Nicotinamide Riboside—The Current State of Research and Therapeutic Uses

Mehmel¹,

Jovanović

Spitz³

2020

Nutrients

159

151

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Nicotinamide riboside (NR) has recently become one of the most studied nicotinamide adenine dinucleotide (NAD+) precursors, due to its numerous potential health benefits mediated via elevated NAD+ content in the body. NAD+ is an essential coenzyme that plays important roles in various metabolic pathways and increasing its overall content has been confirmed as a valuable strategy for treating a wide variety of pathophysiological conditions. Accumulating evidence on NRs’ health benefits has validated its efficiency across numerous animal and human studies for the treatment of a number of cardiovascular, neurodegenerative, and metabolic disorders. As the prevalence and morbidity of these conditions increases in modern society, the great necessity has arisen for a rapid translation of NR to therapeutic use and further establishment of its availability as a nutritional supplement. Here, we summarize currently available data on NR effects on metabolism, and several neurodegenerative and cardiovascular disorders, through to its application as a treatment for specific pathophysiological conditions. In addition, we have reviewed newly published research on the application of NR as a potential therapy against infections with several pathogens, including SARS-CoV-2. Additionally, to support rapid NR translation to therapeutics, the challenges related to its bioavailability and safety are addressed, together with the advantages of NR to other NAD+ precursors.

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“…The viral surface antigen determines both functional and complete cure by its secretion levels in the serum. It also determines the host antiviral response, and its level in blood is positively correlated with intrahepatic HBV replication [27]. The sustained suppression of HBsAg secretion as a functional cure can be pursued or combined with conventional anti-HBV medicines or novel inhibitors of cccDNA formation to complete the treatment.…”

Section: Discussionmentioning

confidence: 99%

QSAR Modeling of a Ligand-based Pharmacophore Derived from Hepatitis B Virus Surface Antigen Inhibitors

Mohebbi¹,

Askari²,

Shaddel³

et al. 2021

Preprint

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Background: Functional cure for Hepatitis B virus (HBV) by inhibiting HBV surface antigen (HBsAg) is crucial. We aimed to develop a predictive quantitative structure-activity relationship (QSAR) model on a ligand-based pharmacophore (LBP) derived from already known HBsAg secretion inhibitors in the present study.Methods: A LBP model was developed using active HBsAg secretion inhibitors as both trainings- and test-sets using LigandScout v3.12 software. The best model with the highest score was used for high throughput screening (HTS) screening of a virtual library comprising 720,000 compounds. A QSAR model was developed by a stepwise multiple linear regression (MLR) on ~2700 descriptors with a confidence interval (CI) of 95%. The test set validated the QSAR model. The goodness of fit statistics evaluated the fitness of the model. A comparable R2 and adjusted R2 were considered as the lack of overfitting. Further RMSE and Q2 statistics were measured for testing the model on the validation set. Principal component analysis (PCA) was also evaluated to estimate the predictor variables' associations and impact on the model.Results: 34 active anti-HBsAg compounds were used to develop an LBP model. 9/34 of compounds with higher clustering pharmacophore-fit scores were tagged as the training set, and the rest of the inhibitors were used as the test set. The best model had a 0.8832 fit score. HTS resulted in 10 potential hit compounds with a fit score of 101.44±0.65. A QSAR model was developed with two response variables, including Yindex and GATS8m, with substantial variance information (p < 0.05). The model was well fitted (R2 = 0.9563, MSE = 0.0023). The model was not predictive on the test set (Q2 = 0.00, RMSE = 0.8153). The PCA results of two factors demonstrated a substantial variance data of both predictor variables. Conclusion: The present study showed a reliable pharmacophore modeling based on known active inhibitors of HBsAg and a well-fitted predictive QSAR model on the LBP. The model can be applied to the chemical libraries fitted to the LBP model, and the QSAR equation would estimate the biological activities of the hit compounds with 95.63% accuracy with only two Yindex and GATS8m descriptors.

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Niacin analogue, 6-Aminonicotinamide, a novel inhibitor of hepatitis B virus replication and HBsAg production

Cited by 18 publications

References 48 publications

An Emerging Application of Cholesterol-lowering Therapy in Inhibition of Rotavirus Infection

An Emerging Application of Cholesterol-lowering Therapy in Inhibition of Rotavirus Infection

Nicotinamide Riboside—The Current State of Research and Therapeutic Uses

QSAR Modeling of a Ligand-based Pharmacophore Derived from Hepatitis B Virus Surface Antigen Inhibitors

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