Nobel Prize in physiology or medicine: why the discovery of hepatitis C virus is of great significance

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 Nobel Prize in physiology or medicine: why the discovery of hepatitis C virus is of great significance


Written by Guo Xiaoqiang

Editor Jin YANAN

In 1947, F.O. MacCallum, an expert on liver diseases in Britain, concluded through analysis that there were at least two types of hepatitis, one of which was transmitted through feces, known as hepatitis A (hepatitis A); the other was transmitted through blood, known as hepatitis B (hepatitis B). This conclusion laid the foundation and direction of hepatitis research.

Discovery of hepatitis virus

If you want to prevent or treat hepatitis, the first step is to find the pathogen. More than ten years after McCullens conclusion about hepatitis, many laboratory researchers around the world tried, but failed. In the mid-1960s, the research was in a deadlock, and most researchers were not optimistic about the prospect of hepatitis. At this time, an accidental discovery changed the status quo. The reason why it is accidental is that the heros original intention is not to study hepatitis.

Baruch Samuel Blumberg, a scientist with both medical and biochemical background, was initially interested in the reasons behind the differences in diseases among different populations, so he collected a large number of blood samples from all over the world. In 1963, when brenberg screened blood samples, he accidentally found that the serum (containing antibody) of a hemophilia patient could react with the blood of an Australian aborigine. Therefore, this unknown component in the blood was called Australian antigen (Australian antibody).

At first, brenberg thought that Australian antibody was a marker of hemophilia. Further screening found that a large number of hepatitis B patients were also positive for Australian antibody. Finally, it was determined that Australian antibody was the component of hepatitis B virus and was renamed as hepatitis B virus antigen. However, the name of Australian antibody is still used today. Brenbergs discovery cleared the way for the study of hepatitis B virus, and he shared the 1976 Nobel Prize in physiology or medicine for his discovery.

In 1973, scientists at the National Institutes of Health (NIH), under the leadership of Steven feinstone, identified hepatitis A virus from the feces of prisoners. So far, both known types of hepatitis viruses have been found.

The identification of the two viruses is of great significance. The first is the establishment of detection methods to ensure the reduction of virus pollution. For example, in 1977, the proportion of blood transmission of hepatitis B caused by hepatitis B virus in the United States was almost zero; the second was the successful development of vaccines. Around the 1980s, Maurice Hillman, an American microbiologist, developed hepatitis A and hepatitis B vaccines successively, which further strengthened the prevention of hepatitis.

At a time when everyone was confident that the hepatitis problem had been basically solved and that they could rest assured in the future, new problems appeared.

Discovery of hepatitis C virus

Harvey James alter, a physician and virologist, was involved in the Australian anti-virus discovery with brenberg. He joined NIH in the 1970s to participate in blood bank quality control to reduce the transmission of hepatitis through blood transfusion. However, in his work, orte found that despite the elimination of hepatitis B virus, blood transfusion can still lead to a large proportion of hepatitis. The detection results of hepatitis A and hepatitis B virus in these infected patients were also negative, thus denying the omission of virus detection. In 1975, orte named this new type of hepatitis as non-A, non hepatitis B, and did not directly call hepatitis C for careful consideration. Orte and others worked with chimpanzees to further prove that the virus that causes the hepatitis is a new type of virus.

The discovery of a new type of hepatitis has prompted scientists around the world to look for pathogens. At first, it was optimistic that virus identification would be completed soon, but it took more than ten years to find the virus. In 1987, Michael Houghton team of Chiron Corporation and Bradley of CDC in USAuff08 DanielW.Bradley uff09A new type of virus was discovered by molecular cloning. In 1988, aults team confirmed that the new virus was present in blood samples from patients with non-A, non-hepatitis B infection. In 1989, the Horton team officially identified the new virus and renamed it hepatitis C virus (HCV).

Several scientists have also received many awards from the scientific community for this contribution (Figure 1). In 2000, ault and Horton shared the famous Lasker Clinical Medicine Award in the United States; in 2013, ault and Bradley shared the Canadian galdena International Award (Holden himself refused).

Figure 1. Three famous HCV Discoverers

Establishment of HCV culture system in vitro

Although the discovery of HCV can reduce the chance of infection, it has not fundamentally eliminated hepatitis C. the development of vaccines and drugs is fundamental. If we want to solve these problems, we need to have a comprehensive understanding of this new virus.

Ralf bartenschlager, a virologist at the University of Heidelberg in Germany, and student Volker Lohmann are also interested in HCV. Lohmann is full of confidence in the establishment of HCV training system, risking the risk of failing to graduate normally, so he chose the research topic, which is quite desperate. After many attempts, in 1999, on the basis of Rices discovery, a HCV in vitro culture system was developed, which can reproduce in human hepatoma cells, greatly simplifying the experimental operation. The rapid acquisition of a large number of HCV from hepatoma cells in vitro has greatly promoted the research of HCV.

Figure 2. Founder of HCV in vitro culture (image from Lasker prize website)

The first trial of knife

Vaccine development is considered to be the basic problem to solve HCV. Unfortunately, HCV is highly variable, which brings great challenges to vaccine development. The 30-year research course shows that the research on hepatitis C vaccine is very difficult. Because the hepatitis C vaccine has not yet been successfully developed, it is regarded as the three major models of vaccine development failure together with HIV vaccine and influenza virus vaccine.

In 1998, two scientists from Emory University, Raymond schanizi and Dennis Liotta, set up a small pharmaceutical company, pharmaset, which is committed to the development of antiviral drugs, and hepatitis C drugs are an important part.

Fig. 3. Mechanism of sofibovir inhibiting hepatitis C virus

For HCV, its pathogenic mechanism is not complex, that is, never-ending reproduction. For parental HCV, the key step in reproduction is to prepare a set of genetic material (RNA) for the offspring virus. The production of RNA requires four kinds of raw materials, namely ATP, GTP, CTP and UTP, and then complete with the help of a kind of RNA polymerase called RNA polymerase. If we can find an ideal raw material analogue, the substance deceives RNA polymerase and substitutes the normal raw material when HCV produces the next generation RNA, once the operation is successful, it will lead to the failure of RNA production, and HCV will lose its reproductive capacity, just like sterilization, and the disease will be naturally treated. This strategy can be called grafting, and the drugs developed are called nucleotide analogues. There is no lack of precedent in the history of drug research, such as azidothymidine (AZT), also known as zidovudine, which was approved for the treatment of AIDS in 1987, is a nucleotide analogue.

For this reason, famaset began to screen nucleotide analogues with HCV in vitro culture system to inhibit HCV RNA production. These candidates were collectively referred to as pharmaset small molecule inhibitor (PSI), and different compounds were numbered. Under the leadership of chemist Jeremy Clark, psi-6130 was finally screened out, which can be converted into a compound very similar to UTP in liver cells (similar to stupid and indistinct), and finally achieve the purpose of inhibiting HCV reproduction (Fig. 3). Famaset then tested it on animal models, and the results were surprisingly good. It almost completely inhibited the reproduction of HCV with few side effects.

Success

Sofia first had a comprehensive understanding of the companys new drug research and development, and had a strong interest in psi-6130 which was temporarily in trouble. After careful analysis, it is concluded that psi-6130 is worth rescuing. In Sofias eyes, psi-6130 is a good candidate drug, but there are structural problems. The biggest problem is that it can not reach the designated site (HCV infected hepatocytes) effectively. Therefore, as long as the structure is modified, psi-6130 can pass through the key points of drug absorption and transportation.

Sofia then launched the psi-6130 upgrade program, produced a series of psi-6130 modifications, and tried to screen out more perfect compounds. After two years of efforts, psi-7977 was finally discovered in 2007. Clinical trials have shown that psi-7977 has ideal absorption effect, and can metabolize psi-6130 in the liver. Further large-scale clinical trials found that psi-7977 combined with interferon and ribavirin, or only combined with ribavirin for 12 weeks, patients with hepatitis C can achieve a cure effect, such a magical effect is almost incredible, after all, anti viral treatment such as AIDS can only control the disease but not cure.

On December 6, 2013, the United States FDA officially approved psi-7977 combined with ribavirin for the treatment of hepatitis C. abandoning interferon is a great progress. In memory of Sofias important contribution in the development of psi-7977, the molecule was renamed sofosbuvir (or translated into sofobuvir and other names) (Fig. 4), and the trade name sovaldi. Sofia also shared the 2016 Lasker Clinical Medicine Award for this important contribution.

It means a lot

Gilead, a famous manufacturing company, seized the business opportunity and acquired famaset for us $11.2 billion in November 2011. Sofibuvir naturally became the main drug of Gilead. Sofibways sales have brought Gilead a lot of money. In the first quarter of 2014, sofibweys sales exceeded $2 billion, and the annual sales were as high as $10 billion. Gilead has developed a series of hepatitis C treatment combination drugs on the basis of sofibovir, so as to further improve the therapeutic effect.

The introduction of sofibuprovir has undoubtedly brought gospel to many patients with hepatitis C. The number of hepatitis C deaths in the United States once exceeded the number of AIDS deaths. The cure of hepatitis C can be achieved after 12 weeks of medication (1 tablet of sofibuprovir and other combined drugs every day), so that this long-term disease without vaccine and specific drug treatment can be fundamentally solved. Because some patients with hepatitis C can further develop into liver cirrhosis and liver cancer, sofibvir can also be regarded as a preventive drug for liver cancer to a certain extent.

Figure 5. Global prevalence of hepatitis C in 1999 (photo from Wikipedia)

Although sofibuprovir has been praised by many patients as a miracle drug for hepatitis C treatment, the high cost still makes many hepatitis C patients flinch. In the United States, the cost of a 12 week treatment with sofibuprovir is as high as $84000, a price that many families find difficult to accept. Fortunately, generic drugs have been sold in India at a price of only $800 to $1000 (a treatment cycle), thus bringing hope to hepatitis C patients in many developing countries.

At present, all parties are making active efforts to make as many hepatitis C patients as possible afford the price of sofibuprovir, so as to make this miracle medicine achieve the purpose of benefiting human beings to the greatest extent.

reference material

[1] Guo Xiaoqiang. Baluch Samuel Blumberg, discoverer of anti hepatitis B Australian antibody. Journal of nature, 2012,34 (5): 308-310

[2]AlterHJ, HoughtonM.ClinicalMedicalResearchAward .HepatitisCvirusandeliminatingpost- transfusionhepatitis.NatMed ,2000,6(10):1082-1086.

[4] PaleseP.ProfileofCharlesM.Rice ,RalfF.W.Bartenschlager, andMichaelJ.Sofia ,2016Lasker-DeBakeyClinicalMed icalResearchAwardees.ProcNatlAcadSciUSA ,2016,113(49):13934-13937.

[5]VilarinhoS, LiftonRP.PioneeringaGlobalCureforChronicHepatitisCVirusInfection .Cell,2016,167(1):12-15.

[6]BartenschlagerRF,RiceCM, SofiaMJ.HepatitisCVirus -FromDiscov erytoCure:The2016Lasker-DeBakeyClinicalMedicalResearchAward.JAMA ,2016,316(12):1254-1255.

Editor: shiny

This years Nobel Prize in physiology or medicine is announced: three winners have uncovered the hidden hepatitis C virus, and the unfinished journey brings the doomsday to hepatitis C. detailed explanation of the 2020 Nobel Prize in physiology or medicine source: Zhang Zutao, editor in charge of the Institute of physics, Chinese Academy of Sciences_ NT5054