Hepatitis B virus (HBV) affects many people around the world and is one of the important causes of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Nucleoside (acid) analogs (NUCs) are mainly taken orally, and past clinical trials have proven that there are few adverse reactions. However, their mechanism of action generally cannot achieve the urgent needs of the current HBV field, that is, hepatitis B surface antigen (HBsAg) and anti-HBs seroconversion, that is, functional cure. The development of
hepatitis B antigen-related inhibitors, an introduction to the mechanism of action of new drugs, including RNAi and NAPs
NA. The advantages of
NA are its mechanism to inhibit HBVDNA and its ease of administration. The development of innovative drugs in the field of hepatitis B focuses more on the mechanism of action that is different from NUCs, and focuses more on the development of new direct-acting antiviral drugs (DAA) that inhibit the level of HBsAg.
In addition, some new NUCs therapies will also cause adverse events. Therefore, efforts will be focused on achieving a functional cure for HBV, identifying new targets and new molecules, and then developing new drugs. Before developing drugs, scientific researchers must first fully understand the complete replication steps of the HBV life cycle. Judging from the latest development progress of global new drugs for hepatitis B, the most ideal method is through combination therapy, that is, the combined use of compounds developed for different steps of the HBV life cycle , , with the hope of achieving a functional cure. This can be seen intuitively in the drug development data in recent years.
For example, virus entry inhibitor , capsid assembly regulator, RNAi, surface antigen inhibitor, toll-like receptor agonist, therapeutic vaccine, etc., all target different steps in the HBV life cycle. The compounds generated by these new therapeutic targets are used in combination, and clinical studies are ongoing to evaluate the safety and effectiveness of the combination.
Previously, Xiaofan Health has introduced that the development of new drugs for hepatitis B virus mainly focuses on three major directions, namely inhibiting HBV replication, inhibiting HBV antigens and new immunomodulator drugs. New hepatitis B drugs under development that can directly affect the level of hepatitis B surface antigen should be said to be much more cutting-edge than the current nucleosides. Let us temporarily call them inhibitors that affect HBV antigens. They mainly include viral entry inhibitors, RNA interference (siRNA and ASO), and hepatitis B surface antigen release inhibitors.
Hepatitis B new drug development data for entry inhibitors have been published in major pharmaceutical companies and academic journals in recent years. The development characteristics of this new class of HBV compounds are mainly based on subcutaneous administration and work by blocking the sodium-taurocholic acid co-transporting polypeptide (NTCP) receptor used by the hepatitis B virus to enter liver cells.
small interfering RNA (siRNA), these novel HBV compounds work by binding to complementary viral mRNA in the cytoplasm, triggering its elimination. Antisense oligonucleotides (ASO), these novel HBV compounds target all HBV RNA and induce cleavage of HBV RNA in the nucleus and cytoplasm through RNase H1. Surface antigen inhibitors, the most common of which are nucleic acid polymers (NAPs), their mechanism of action is to block the release of hepatitis B surface antigen from hepatocytes and enhance the host-mediated HBV clearance mechanism.
Nowadays, major pharmaceutical companies around the world have developed innovative hepatitis B drugs with the above new mechanisms of action. These new compounds are mainly targeted at hepatitis B surface antigen. Therefore, we can also classify them as inhibitors of hepatitis B virus antigens. They work by interfering with different mechanisms responsible for the virus entry pathway, the production of virus particles and antigen , and affecting virus assembly.
RNA interference, the most common ones are siRNA and ASO. As mentioned before, the mechanisms between them are very similar. This large class of compounds targets the RNA of hepatitis B virus, thereby blocking the production of antigens.
