Concept of Viral Inhibitors via NTCP

Abstract

Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an entry receptor for hepatitis B and D viruses (HBV and HDV) has not only promoted our understanding of the mechanism underlying the viral entry process, but also provided cell culture models supporting viral infection. These models have greatly facilitated cell-based chemical screening for the discovery of entry inhibitors, and mode of action studies using such inhibitors have shown the advantages of NTCP as a drug target. Furthermore, in vitro chemical screening by application of high-throughput affinity-based technologies that target NTCP has identified a variety of unique small molecules that interfere with viral entry. This review summarizes this hot topic in the development of HBV/HDV entry inhibitors, with special focus on the use of NTCP as a drug target.

Selective hepatitis B and D virus entry inhibitors from the group of pentacyclic lupane-type betulin-derived triterpenoids

“…A promising novel drug target to block HBV/HDV virus entry into hepatocytes is represented by the Na + /taurocholate co-transporting polypeptide NTCP (gene symbol SLC10A1 ), which has been identified as the bona fide hepatic receptor for HBV/HDV 9 , 10 . It is generally accepted that HBV/HDV entry into hepatocytes essentially involves attachment of the virus particles to heparan sulfate proteoglycans 11 , followed by high-affinity binding of the myr-preS1 domain of the large envelope protein to certain domains of NTCP that finally triggers subsequent steps such as endocytosis of the virus-receptor complex 12 .…”

“…These data clearly indicate that NTCP is an appropriate drug target to control hepatic HBV/HDV levels. In addition, an HBV/HDV entry inhibitor addressing NTCP might be beneficial to prevent new infections of hepatocytes during chronic infection with HBV/HDV 12 .…”

Role of Biomarkers in Guiding Cure of Viral Hepatitis B

“…120,121 This variant has also been linked with a lower susceptibility to develop CHB. 120 These findings could have therapeutic implications, a view that is supported by an in vitro study where cyclosporine A and its analogues inhibited HBV entry into cultured hepatocytes by targeting the NTCP membrane transporter, 122 and a study in patients with chronic hepatitis delta treated with myrcludex. 123 Some variants of the IFN lambda (IFNL) gene such as IFNL3/IFNL4 have been associated with hepatic inflammation and fibrosis in CHB and in chronic hepatitis C. 124 A noninvasive decision model named FIBROGENE, which includes clinical data and IFNL3/IFNL4, has a very high negative predictive value (> 0.96) for ruling out cirrhosis in patients with CHB.…”

Medicinal chemistry strategies toward host targeting antiviral agents

“…The other discovered NTCP inhibitors include FDA approved drugs (ie, CsA, 123 ezetimibe, and ritonavir, 124 etc), fasiglifam, 125 oxysterol, 126 vanitaracin A, 127 NTI007, 128 and among others. 129 The inhibition of NTCP by these inhibitors normally will result in the loss of transporter function of NTCP, leading to the inhibition of bile acid uptake, which might cause unwanted adverse effects. Interestingly, Shimura et al 130 derivatives with anti-HBV activity in vitro via direct interaction with NTCP to inhibit viral attachment.…”