Heavy Bomb - The Research and Development Process of Sofebwe

Hepatitis C (hepatitis C) is viral hepatitis caused by hepatitis C virus (HCV) infection, more than 150 million people worldwide infected with HCV, and 10 million people in China are infected with hepatitis CThe disease is strong lysing, infected people often have no symptoms or symptoms are very light, easy to be ignored by patientsBut it will quietly erode people's health and gradually develop into cirrhosis and liver cancerIt is reported that 20 years after hCV infection, the incidence of cirrhosis of the liver is nearly 10 to 15%About half a million people undergo liver transplants or die each year as a result of hepatitis C and its complications, so hepatitis C is also known as the "silent killer"there are currently two options for treating hepatitis C: PR (polyglycol interferon combined with ribavirin) and DAAs (direct antiviral drug, direct-acting antivirals)However, the PR program has obvious disadvantages, 24 to 48 weeks of injection of polyethyl glycol interferon and the use of the antiviral drug ribavirin, but this treatment is expensive and toxic side effects, the overall cure rate of 54%-56%, and the length of the drug is not convenientThe overall cure rate of the DAAs program that followed suddenly increased to more than 90%, and some were able to achieve a cure rate of 100%, and the time taken was short, mostly oral, convenient medication, so that hepatitis C became a curable diseaseSofosbuvir, as this article, is the leader in DAAs drugs, which has been approved by the FDA in 2013, becoming one of the most important new drugs approved for the year and quickly becoming a "heavy bomb."Sofibuwe Chemical StructureThe structure of HCV and the DAAs drugHCV belong to the single-stranded justice RNA virus, which mainly contains 6 genotypesAfter extensive research, scientists have found that the replication of HCV involves three important drug targets: (1) NS3/4A protease - associated with HCV polyprotein transcribed processing; (2) NS5B polymerase - key enzyme salycating HCV RNA synthesis; and (3) NS5A protein - associated with the formation of replication complexesNS3 /4A protease inhibitors include drugs such as trappivir and poprevir, and NS5A protein inhibitors include dakatamivir, redipaver, etcSofebwe belongs to the NS5B polymerase inhibitor, which, when combined with the target, can terminate viral RNA replication, which is the "ultimate trick" to eliminate HCVIt is also the first drug to treat hepatitis C without the need for combined interferon and has an effect on all genotype HCVThe design and exploration of RNA replication of membrane-related HCV the design of potential DAAs compounds
the discovery of Sofebwe began with the study of HCV NS5B RNA dependence RNA polymerase (HCV NS5B RNA polymerase, or HCV NS5B RdRp) HCV NS5B RdRp is an important enzyme for HCV, and Gly317-Asp318-Asp319 (Asp319(Asp319) that dominates HCVNS5B RdRp is an unchanging argonine residue that is present in all HCV genotypes Nucleoside triphosphate (NTP) binds to the GDD site to extend the HCV RNA chain Therefore, HCV NS5B RdRp is an incomparable active target target, the next step is to design inhibitors that bind to the target It is common practice to design nucleoside analogues, the design of compounds should pay attention to two points: 1 the amount of toxicity caused by off-targeting with RNA polymerase, 2 the activity of the compound itself and whether to participate in in vivo nucleic acid metabolism Designing non-targeting, low-toxic and highly active compounds is the key to DAAs drugs a large amount of experimental design and accumulated experience by scientists, who screened out a urethra analogue for testing as a potential drug Experience has shown that there will be significant anti-HCV activity at the unique substitution base of the C2' or C4' bit of the urinric The results showed that PSI-6130 as a ureg analogue (the C2'bit of urinric sin replaced by F atoms and methyl) showed an effective inhibitory effect on HCV replication Unfortunately, clinical Phase I trialresults show that PSI-6130 has no good pharmacokinetic characteristics, while for another compound, PSI-6206, it has good tolerance and high-efficiency inhibition, but it also has drawbacks - its bioavailability is too low, at only 25% So the two compounds came out to address bioavailability and metabolism problems, the 3', 5'-dibutybutylaterl pre-drug RG7128 (mericitabine) was designed to promote the absorption and metabolism of compounds in the intestines The results do show that the mericitabine improves the pharmacokinetic parameters, and clinical trials have shown that the drug has some efficacy But the drug is not the ideal one, because the negative conditions of the general effect and short half-life of the mericitabine prevent it from growing into a good drug THE chemical structure of the liver target nucleotide pre-drug design exploration
Mericitabine drug has a shorter half-life, need to take the drug twice a day, the design of more effective, long half-life drugs are more conducive to patient treatment For the safety and efficiency of the drug, the C2' bit is retained by F atom and methyl Observations of PSI-6130 metabolites show that monophosphate PSI-6130 can be converted into the form of triphosphate, the triphosphate PSI-6130 is the active metabolite, and surprisingly, the single phosphate PSI-6130 can be further converted to triphosphate PSI-6206, and the triphosphate PSI-6206 has a long half-life, the activity is better than the triphosphate PSI-6130 However, PSI-6206 cannot be converted to PSI-6206 of triphosphate the metabolic pathways and products of PSI-6130 this is a major finding, suggesting that monophosphate urethra derivatives may be the ideal DAAs drug to grow The big question now is how to pass the monophosphate urethra derivative stogiton to the body Compounds containing phosphate groups are rather unfriendly to the body because they are negatively electrical In the end, scientists were still using the pre-drug design, and through extensive experience and SAR research, the first pre-drug PSI-7672 was designed After that, a large number of derivatives were also synthesized and some experience was summed up For R1 and R2 groups, methyl, isopropyl, butyl and benzene are commonly used to replace the group, while the replacement base of the R3 group is mostly benzene and its derivatives Further experiments showed that it was more appropriate for the R2 position to be replaced by methyl because other groups showed toxic reactions and were L-shaped the determination of The R1 and R3 groups was also very difficult, the scientists conducted animal experiments on the candidate compounds, only the compounds number10, 11, 16 showed high concentrations in the liver of rats, followed by experiments in dogs and monkeys In subsequent experiments, compounds 10 and 16 were eliminated due to toxic reactions, while compound11 was retained for good safety, pharmacokinetic parameters and a long half-life, and was an efficient HCV inhibitor that prevented the virus from replicating the structural display of the candidate compound , the compound was clinically tested, and The Phase I trial showed that it had good safety and pharmacokinetic parameters and could do it once a day, and that the patient's tolerance was high and a successful drug However, for compound 11, it is not a monomer, but a mixture of different hand types Scientists then invented a hand-synthetic method and found that the S-constructed compound sat out of activity The S-constructed compound is Sofibuwe Sofebowe has a strong inhibitory effect on HCV NS5B RdRp, which has an EC90-0.42 sM, and is active for all genotype HCV S-form compound is the only drug successfully marketed for sofebwee small for drugs that target HCV NS5B polymerase Sofibwe is also the first drug that does not require the use of interferon in combination The successful development of NS5B inhibitors, also a revolutionary anti-HCV therapy, makes it possible to cure hepatitis C References: 1 Sofosbuvir: A novel treatment option for chronic hepatitis C infection 2.Discovery of sofosbuvir: a revolution for therapy of chronic of the hepatitis C.
3 Sofosbuvir: The Discovery of A Curative The Treatment for The Treatment of The Phytos C Virus 4.Sofosbuvir: a novel agent for chronic oral loral C.
5 Structures of the hepatitis C virusnonstructure proteins required for replicase assembly and function 6.https://