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Antonín Holý 85 – Story of tenofovir

1 September 2021
Antonín Holý 85 – Story of tenofovir

Antonín Holý (1 September 1936 – 16 July 2012), chemist and former director of IOCB Prague, was born on this day 85 years ago. During his fruitful career, Holý had discovered several compounds which made it to approved drugs, such as dihydroxypropyladenine (Duvira gel) used to treat infections caused by the herpes simplex virus or acyclic nucleoside phosphonates (ANPs): cidofovir, adefovir, and the best known tenofovir.

ANPs were discovered in collaboration with Erik De Clercq from the Rega Institute for Medical Research at KU Leuven, Belgium, with the aim of developing metabolically stable isopolar and isosteric nucleotide analogues. The ANP analogues exhibit a unique spectrum of antiviral and antitumor activity.

Holý and De Clercq submitted the key patent applications for ANPs in the years 1985 and 1986. The license to their utilization was sold to Bristol-Meyers (USA), and preclinical trials commenced in 1987. Extensive research continued at Bristol-Meyers for the next two years. In 1989, Bristol-Meyers merged with another pharma company, Squibb, and the development of ANPs was stopped. Fortunately, the license agreement contained a forethoughtful paragraph: “In the event development is discontinued, all rights must be returned to IOCB together with all materials, obtained results, and documentation.”

John C. Martin, director of antiviral chemistry at Bristol-Meyers Squibb, and the third key person of the story, realized the therapeutic potential of these compounds and decided to continue in their development. He raised money and moved his team of 14 researchers to a small biotechnology company in California called Gilead Sciences. Gilead then newly licensed the ANP patents from IOCB and the Rega Institute. Cidofovir and adefovir were selected as the most promising compounds for development. Tenofovir was added later.

Finally, four compounds of the ANP group including two prodrugs of tenofovir developed by Gilead – tenofovir disoproxil fumarate and a few years later tenofovir alafenamide fumarate – were approved for therapeutic use in human medicine and introduced to the market. Drugs based on tenofovir revolutionized therapy for HIV and HBV patients – they have helped save millions of lives and have also dramatically improved the quality of life for AIDS patients.

The collaboration of Antonín Holý, Erik De Clercq, and John C. Martin established a long-lasting relationship between IOCB, the Rega Institute, and Gilead Sciences.

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