Identifizierung und Testung niedermolekularer HBV/HDV Entry-Inhibitoren
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Beschreibung
Infections with hepatitis B (HBV) and D virus (HDV) are the main cause of liver carcinoma as a result of chronic hepatitis. Despite the availability of vaccination against HBV, which also successfully protects against HDV infections, more than 800,000 people annually die from this serious disease, mainly in poor regions of the world. Antiviral therapies using interferons and/or nucleos(t)id analoga are usually sufficient to keep chronic hepatitis under control. However, these therapeutics usually have to be given livelong causing some serious side effects. Furthermore, the chance of curation is very low.
In 2012, however, a new field of therapeutic opportunities opened up, as the "Na+/taurocholate cotransporting polypeptide" (NTCP, gene symbol: SLC10A1) was identified as the specific hepatocellular receptor for HBV and HDV. Previously, NTCP was known to be a sodium-coupled transporter of bile acids expressed at the basolateral membrane of hepatocytes. There it delivers bile acids from the portal blood back to the liver. Thus, NTCP represents an important component of the enterohepatic circulation of bile acids.
Due to its second function as receptor for HBV and HDV, NTCP represents an interesting drug target. Blocking of NTCP with small molecules is an attempt to prevent the entry of the two mentioned viruses. In 2020, a first so-called entry inhibitor was approved for therapy of HDV infections. It represents a synthetic peptide with the brand name Hepcludex®, which originates from the viral envelopes of HBV and HDV and binds to NTCP after subcutaneous application. This makes NTCP inaccessible for virus binding. However, due to the particular need for therapeutics in poor regions of the world, an entry inhibitor based on an injectable peptide drug is not optimal, since storage and transport requirements are difficult to guarantee. In addition, many substances, including the above-mentioned peptide, also inhibit the bile acid transport function of NTCP, thus interfering with bile acid homeostasis.
The present study demonstrates that structure-activity relationships can be defined for selective inhibition of the viral receptor function of NTCP without tackling its bile acid transport function. Among the group of betulin derivatives, 3,28-di-O-acetyl-29-hydroxybetulin showed the best profile with an IC50 of preS1 peptide binding inhibition of 8 µM and selectivity index of 125. Among the propanolamine derivatives, compound A000295231 showed the best performance with IC50 of 16 µM and selectivity index of 65, respectively.
In addition, the uniform experimental procedure of the present study generated a large dataset enabling further bioinformatics processing by using pharmacophore and QSAR models. A virtual screening could already be performed that identified novel, potential oral HBV/HDV entry inhibitors. Among them, compound ZINC000253533654 showed the best activity against preS1 peptide binding with an IC50 of 9 µM, which was also confirmed by in vitro infection experiments. Unfortunately, the selectivity index of this compound was low at 1. Nevertheless, the data and findings obtained are suitable to perform molecular drug design and to develop a drug that selectively blocks virus binding to NTCP without affecting bile acid circulation, with simple oral administration of the drug.
The overall outcome of the present study is an experimental and virtual screening platform suitable for identification of potent and virus-selective HBV/HDV entry inhibitors. The concepts of selectivity, target specificity and substrate specificity explained in chapter 3 are basic components of this platform and pioneer in the further development of HBV/HDV entry inhibitors from the group of small molecules.
Autor*in
Michael Kirstgen
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Gelbsucht Hepatitis Virale Erkrankungen