The author's series on new drug discovery has been compiled into a book, published by Tsinghua University Press, entitled Minimalist History of New Drug Discovery.I would like to thank you for your guidance and assistance on the ScienceNet platform and academicians, experts and colleagues.If you are interested in oseltamivir and paramivir, you can check it out.
Oseltamivir, which is used to fight the flu virus, has become a hot drug in medical institutions.The Beijing Food and Drug Administration this week launched an emergency deployment to ensure the supply of oseltamivir.
How was oseltamivir discovered?
Austrian scientist Norbert Bischofberger (1954-) received his doctorate in organic chemistry from the ETH Zurich and went to Harvard University to do post-doctoral research.1986-1990 He worked for Genetech, then moved to Gilead as director of organic chemistry.
Gilead Corporation by Michael L. Michael L. Riordan 1958- ) was established on 22 June 1987.Lyldon earned a doctorate in medicine from Johns Hopkins University and went to Harvard Business School.He had dengue fever, so after a few years in the investment industry, based on his medical background, he teamed up with several scientists to set up Gilead to develop antiviral drugs.He set the company's goal at the forefront of international drug development and offered invitations to senior government officials, Nobel laureates, and investment gurus, franchisees, or directorships (Buffett was also invited, but he refused).In 1992, the company went public on the New York Stock Exchange without any profit.
At this time, Gilead's research and development funds were sufficient, and the newly hired Bishov Berger also had a relatively independent work independence.In October 1992, Bischoffberg discovered a poster of Mark Von Itzstein, Department of Pharmaceutical Chemistry, at the Interdisciplinary Conference on Antimicrobial Preparations and Chemotherapy (ICAAC).
He immediately realized that this was a very important target, and that since zanamivir was an inhaler that did not fit the habits of flu patients, if developed for export, there would be a bigger market.So he suggested the development of oral neuraminidase inhibitors.Gilead immediately formed a team to develop an oral neuraminidase inhibitor because of the advice to fit the market, targeting the frontier, and the company's initial public offering of large sums of money.
After computer-aided design, the researchers first obtained a highly reactive compound GS4071, but encountered problems that could not be absorbed through the gastrointestinal tract as well.However, they modified the compound to obtain GS4104, reducing its polarity, making it readily absorbed through the digestive tract, and then metabolizing it into oseltamivir carboxylate, the active substance of GS4071.The drug precursor GS4104 was named oseltamivir phosphate.
In vitro, the virus replication was observed by treating GS4071 virus (cell culture), and the inhibitory IC50 of GS4071 on neuraminidase was detected by GS4104 was administered orally to infected mice, and mortality was observed.Ultimately, oseltamivir is effective against influenza.
In 1995, relevant in vitro experiments have determined that the drug is effective and safe and can be applied for clinical trials in vivo.But Gilead is short of money.Over the years, developing anti-HIV drugs, researching anti-tumor drugs, and acquiring other companies' active molecules have cost the company nearly $100 million, but none of them are on the market.Only in 1995 was a new drug approved for use in the treatment of AIDS-related giant cell viral retinitis.
No way, the company decided to transfer oseltamivir exclusively to Roche.In 1996, the two sides signed a transfer agreement.The problem facing Roche is the big production process.Oseltamivir was originally used by Gilead as a starting material for quinic acid but the quinic acid itself was deficient.The Roche chemists Martin Karpf and René Trussardi experimented to synthesize shikimic acid, which is mainly extracted from Chinese star anise and can be imported from China.Later, Roche further developed a process to produce intermediates from recombinant E. coli, reducing production costs.
After intensive clinical trials, oseltamivir was approved by Switzerland in September 1999 and marketed as the world's second neuraminidase inhibitor under the trade name Tamiflu.In October, the U.S. FDA approved its application.The first drug of its kind, Zanamivir, was approved by the FDA in July 1999 under the trade name Relenza, only three months ahead of it.
Zanamivir and oseltamivir were neck and neck in the flu of the year it went on sale.But in 2005, the H5N1 flu outbreak in Southeast Asia was detected when oseltamivir was detected to inhibit the virus.In many countries, the health sector immediately purchased large amounts of reserves.The supply of this product is short of demand.In November, U.S. President George W. Bush asked Congress for an additional $1 billion to buy the drug, after Congress had approved $1.8 billion.It became Roche's flagship product and contributed significant royalties to Gilead.