Anti-HBV clinical use drugs and research drugs

Author: Road Extension

Currently, there are around 240 million people are infected with hepatitis B virus (HBV), and our country is the hepatitis B virus is endemic countries, estimated that currently China has 90 million chronic hepatitis B patients, Of these, 28 million require treatment and 7 million require urgent treatment for serious liver disease and cancer risk. About 15%-40% of patients with chronic hepatitis B develop severe liver disease, and about 750,000 people die every year from hepatitis B and its complications, including hepatocellular carcinoma, cirrhosis, and liver failure. Currently, hepatocellular carcinoma has become the world’s second largest cancer killer.

 Brief introduction of anti-hepatitis B virus clinical use drugs and research drugs

HBV virus pictures

Clinical anti-HBV drugs

At present, commonly used anti-HBV drugs are immunomodulatory drugs and nucleic acid analogs, and immunomodulatory drugs include interferon (IFN), thymosin α1 and cytokines, and nucleic acid analogs. Mainly including lamivudine, telbivudine, entecavir, adefovir, tenofovir.

IFN is a glycoprotein that has antiviral and immunomodulatory effects. When the virus invades the body, it triggers the production of IFN, which then binds to specific receptors on the cell surface to produce antiviral proteins (AVP), which degrade viral mRNA and inhibit viral replication. IFN simultaneously enhances the activity of macrophages and T lymphocytes and enhances the antiviral ability of the body, but the half-life of IFN is very short. In order to prolong the half-life of IFN, pegylated interferon is gradually developed. Although IFN has high antiviral activity, the price of the drug is high, and the treatment cost for long-term use is high, and a considerable portion of patients have serious side effects, and cannot be administered orally, causing inconvenience to the patient, and thus only one A small number of patients with chronic hepatitis B can use it.

The main function of thymosin α1 is to promote the differentiation of T cells into a mature stage and enhance the response to antigens and other stimulants, helping the host to protect against chronic HBV infection and moderate antiviral effects. It can be used in combination with IFN to treat chronic hepatitis B, which has fewer side effects, but it can only be administered by injection.

Lamifudine is a pyrimidine nucleoside drug and the first drug used to treat chronic hepatitis B. It is a reverse transcriptase inhibitor that inhibits HBV replication and reduces viral DNA replication by inhibiting reverse transcriptase activity. The drug can be administered orally and has a high bioavailability. Telbivudine specifically and highly selectively binds to HBV, which is more potent than lamivudine and can be used in pregnant women.

Entecavir is a guanine nucleoside drug and a potent inhibitor of HBV polymerase. Entecavir inhibits HBV by 300 times that of other nucleic acids. Adefovir is a purine nucleotide prodrug that is phosphorylated first after entering the body. Adefovir diphosphate is the activity of inhibiting the virus. It is similar to the dATP required for viral replication and can be “disguised”. dATP, involved in the replication of viral DNA, once Adefovir diphosphate enters the DNA strand, the synthesis of this DNA strand ceases. However, taking this medicine in large doses can cause severe nephrotoxicity. Tenofovir is an acyclic adenine nucleotide analogue and a reverse transcriptase inhibitor. Similar to adefovir, tenofovir must also be converted to tenofovir. effect. The drug has a strong inhibitory effect and is highly resistant to drug resistance.

As nucleoside drugs, they have a common shortcoming, and after a period of use, resistance will occur. At present, the Chinese Society of Liver Diseases recommends peginterferon, tenofovir, and entecavir as first-line drugs, and other drugs as second-line drugs. These drugs can reduce the incidence of liver failure and hepatocellular carcinoma, and improve survival, but can not eliminate the complete hepatitis B virus.

Investigation of anti-HBV drugs

MCC-478

MCC-478 is a derivative of adefovir and has now entered Clinical trials, preclinical studies have shown that it has high anti-HBV activity. Its mechanism of action is similar to that of adefovir, which exerts an antiviral effect by inhibiting viral DNA replication. MCC-478 is effective against wild-type HBV and lamivudine-resistant mutants.

RNAi Drugs

RNAi therapy has been shown to directly target HBV messenger RNA (mRNA) and is highly specific. The use of small non-coding RNAs to regulate DNA expression can effectively reduce HBsAg production and restore immunity. Studies have shown that RNAi successfully inhibits the replication of HBV virus, so this technology has attractive prospects in the treatment of HBV. Because RNA is extremely susceptible to degradation, the primary problem with RNAi therapy is how to deliver the drug to the body and function. At present, pharmaceutical companies have begun to solve this problem. Some companies have developed a dynamic polymer system (Dynamic PolyConjugates /DPC) for targeted delivery of siRNA to the cytoplasm of hepatocytes, reducing the degradation of RNAi and the potential for potential toxicity.

HBV nucleocapsid assembly regulator

AL-3778 is an oral hepatitis B virus nucleocapsid assembly regulator currently in clinical practice Among the Phase II trials, there are hopeful successful drugs. Clinical studies have shown that AL-3778 is well tolerated in patients with chronic hepatitis B. The adverse events are mainly grade 1 and grade 2, and are transient, with no serious life-threatening adverse events. HBV DNA and HBV RNA were observed to have a dose-dependent decrease after treatment, which effectively interfered with the process of HBV encapsidation assembly.

GLS-4 is also a modulator of hepatitis B virus nucleocapsid assembly, and its mechanism of action is similar to that of AL-3778. Studies have shown that the drug is safer and less toxic to human hepatocytes and is currently in clinical phase II studies. Similar drugs in clinical trials include Morphothiadin (clinical phase II), RO6864018 (clinical phase II), AIC 649 (clinical phase I), JNJ56136379 (clinical phase I), HBV CpAM (preclinical), AB-423 (clinical) Before).

HBsAg release inhibitors

Nucleic acid polymers (NAPs) have the activity of inhibiting HBV virus, making phosphorothioate oligonucleotides (PS- ONs) inhibit protein interactions and reduce the secretion of HBsAg. The drug is currently in Phase I and Phase II clinical trials. REP2139-Ca is also an inhibitor of HBsAg release. Studies have shown that this drug can effectively reduce HBsAg in serum and increase interferon and thymosin at 20-38 weeks, which can effectively reduce the DNA content of HBV. The drug is currently in Phase I and Phase II clinical trials.

Entering Enzyme Inhibitors

CyclosporineA is a polypeptide consisting of 11 amino acids. It is being studied as an anti-HBV entry enzyme inhibitor. Inhibitory factors, and later studies have said that the drug can bind to NTCP receptors, NTCP receptor inhibitors can prevent HBV from entering cells. Derivatives of Cyclosporine A (such as SCYX618806, SCYX827830, SCYX1454139) have a stronger activity than Cyclosporine A.

Cyclophilin Protein Inhibitors

In humans, there are seven Cyclophilin proteins, namely CYPA, CYPB, CYPC, CYPD, CYPE, CYP40. CYPs are a must for a variety of viral replications, including HBV and HCV. CYPA has been shown to play an important role in HBV replication and in the secretion of HBV envelope proteins by hepatocytes. As a CYP inhibitor, Alisporivir or NIM811 can effectively block CYP enzyme activity and reduce DNA replication and secretion of HBV.

NVP018 is a second-generation CYP inhibitor and is used orally, increasing patient compliance. In vitro studies have not only inhibited HBV replication, but also affected IFN regulatory factors, which in turn caused immune regulation and played multiple anti-HBV effects.

Summary

At present, anti-hepatitis B virus therapy is emerging, and various new targets are constantly being researched. The above new drugs are only representative of many therapies, except for the above examples. There are TLRs agonists, antisense oligonucleotides, Helioxanthin analogues, immunological checkpoint inhibitors, therapeutic vaccines and other drugs in the study, I believe that in the near future, HBV virus will also be overcome by humans.

Reference:

1.High rates of viral suppression afterlong-term entecavir treatment of Asian patients with hepatitis B eantigen-positive chronic hepatitis B.

2 .Drugs in Development for Hepatitis B

3.Review article: novel therapies for hepatitis B virus cure—advances and perspectives.

4.Treatment of Hepatitis B: A Concise Review

5.Anti-HBV Drugs: Progress, Unmet Needs, and New Hope.

6.Dysregulation of retinoic acid receptor diminishes hepatocyte permissiveness to hepatitis B virus infection through modulation of sodium taurocholate cotransporting polypeptide ( NTCP) expression.

7.Curing a viral infection by targeting thehost: the example of cyclophilin inhibitors.

8.http://www.drugbank.com.