Clinical effects of NTCP‐inhibitor myrcludex B

Cheng, Dongliang; Han, Bing; Zhang, Wei; Wu, Wei

doi:10.1111/jvh.13490

Cited by 29 publications

(26 citation statements)

References 38 publications

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“…The inhibitory effect of Nb87 on myr-preS1 binding reveals the therapeutic potential of molecules that stabilize NTCP inward-facing state(s), as allosteric inhibitors of viral cell entry. Such molecules could constitute alternative and/or synergistic therapeutic tools to existing lipopeptides that mimic high-affinity myr-preS1 binding 23 , 47 , as well as neutralizing antibodies against HBV 48 , 49 .…”

Section: Discussionmentioning

confidence: 99%

Structural basis of sodium-dependent bile salt uptake into the liver

Goutam

Ielasi

Pardon

et al. 2022

Nature

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The liver takes up bile salts from blood to generate bile, enabling absorption of lipophilic nutrients and excretion of metabolites and drugs1. Human Na+–taurocholate co-transporting polypeptide (NTCP) is the main bile salt uptake system in liver. NTCP is also the cellular entry receptor of human hepatitis B and D viruses2,3 (HBV/HDV), and has emerged as an important target for antiviral drugs4. However, the molecular mechanisms underlying NTCP transport and viral receptor functions remain incompletely understood. Here we present cryo-electron microscopy structures of human NTCP in complexes with nanobodies, revealing key conformations of its transport cycle. NTCP undergoes a conformational transition opening a wide transmembrane pore that serves as the transport pathway for bile salts, and exposes key determinant residues for HBV/HDV binding to the outside of the cell. A nanobody that stabilizes pore closure and inward-facing states impairs recognition of the HBV/HDV receptor-binding domain preS1, demonstrating binding selectivity of the viruses for open-to-outside over inward-facing conformations of the NTCP transport cycle. These results provide molecular insights into NTCP ‘gated-pore’ transport and HBV/HDV receptor recognition mechanisms, and are expected to help with development of liver disease therapies targeting NTCP.

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Section: Discussionmentioning

confidence: 99%

Structural basis of sodium-dependent bile salt uptake into the liver

Goutam

Ielasi

Pardon

et al. 2022

Nature

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“…It is the first entry inhibitor capable of inactivating NTCP in vitro and in vivo , and does so by interacting with HBV particles and competing for NTCP receptors. The concentration that blocks HBV and HDV entry is 100-fold lower than that required to inhibit bile acid transport by NTCP ( Volz et al, 2013 ; Bogomolov et al, 2016 ; Cheng et al, 2021 ). At present, Myrcludex B has been approved in Europe for the treatment of patients with chronic HDV infection under the trade name Hepcludex ® ( Takemori et al, 2022 ).…”

Section: Sodium Taurocholate Co-transporting Polypeptide As a Target ...mentioning

confidence: 99%

Regulation of the HBV Entry Receptor NTCP and its Potential in Hepatitis B Treatment

Zhou

2022

Front. Mol. Biosci.

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Hepatitis B virus (HBV) is a globally prevalent human DNA virus responsible for more than 250 million cases of chronic liver infection, a condition that can lead to liver inflammation, cirrhosis, and hepatocellular carcinoma. Sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes and a mediator of bile acid transport, has been identified as the receptor responsible for the cellular entry of both HBV and its satellite, hepatitis delta virus (HDV). This has led to significant advances in our understanding of the HBV life cycle, especially the early steps of infection. HepG2-NTCP cells and human NTCP-expressing transgenic mice have been employed as the primary cell culture and animal models, respectively, for the study of HBV, and represent valuable approaches for investigating its basic biology and developing treatments for infection. However, the mechanisms involved in the regulation of NTCP transcription, translation, post-translational modification, and transport are still largely elusive. Improvements in our understanding of NTCP biology would likely facilitate the design of new therapeutic drugs for the prevention of the de novo infection of naïve hepatocytes. In this review, we provide critical findings regarding NTCP biology and discuss important questions that remain unanswered.

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“…Bulevirtide has appeared as an entry inhibitor, which can inactivate HBV receptors and compete with HBV for the sodium-taurocholate co-transporting polypeptide. Thus, it can block the HBV infection in hepatocytes and also accomplish HBV transcriptional suppression [53]. However, data from randomized clinical trials on its utility have yet to emerge.…”

Section: Ongoing and Future Innovative Treatment Modalities Targeting The Virusmentioning

confidence: 99%

Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical

Akbar

Mahtab

Aguilar

et al. 2021

Exploration of Medicine

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With the advent of various vaccines and antimicrobial agents during the 20th century, the control and containment of infectious diseases appeared to be a matter of time. However, studies unveiled the diverse natures of microbes, their lifestyle, and pathogenetic potentials. Since the ground-breaking discovery of the hepatitis B virus (HBV) by Baruch Blumberg and the subsequent development of a vaccine in the early 1980s, the main task of the scientific community has been to develop a proper management strategy for HBV-induced chronic liver diseases. In the early 1980’s, standard interferon (IFN) induced a reduction of HBV DNA levels, followed by the normalization of serum transaminases (alanine aminotransferase, ALT), in some chronic hepatitis B (CHB) patients. However, in the course of time, the limitations of standard IFN became evident, and the search for an alternative began. In the late 1980’s, nucleoside analogs entered the arena of CHB treatment as oral drugs with potent antiviral capacities. At the beginning of the 21st century, insights were developed into the scope and limitations of standard IFN, pegylated-IFN as well as nucleoside analogs for treating CHB. Considering the non-cytopathic nature of the HBV, the presence of covalently closed circular DNA (cccDNA) in the nucleus of the infected hepatocytes and HBV-induced immune-mediated liver damages, a new field of CHB management was initiated by modulating the hosts’ immune system through immune therapy. This review will discuss the nature and design of innovative immune therapy for CHB.

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Clinical effects of NTCP‐inhibitor myrcludex B

Cited by 29 publications

References 38 publications

Structural basis of sodium-dependent bile salt uptake into the liver

Structural basis of sodium-dependent bile salt uptake into the liver

Regulation of the HBV Entry Receptor NTCP and its Potential in Hepatitis B Treatment

Exploring evidence-based innovative therapy for the treatment of chronic HBV infection: experimental and clinical

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