Obituary William H. Prusoff (1920–2011): Father of Antiviral Chemotherapy Yung-Chi Cheng* Yale School of Medicine, New Haven, Connecticut, United States of America Regarded as the father of antiviral by Dr. Jerome Horwitz had potent anti- chemotherapy, William H. Prusoff (Bill) HIV properties. The compound was passed away on April 3, 2011, in New originally named D4T, and Bristol-Myers Haven, Connecticut. Dr. Prusoff spent Squibb developed and marketed this drug most of his career studying analogs of under its more common name, Zerit. It thymidine, a nucleoside building block of became a key drug as part of the first DNA, with an eye toward developing combination therapy for treating AIDS. therapeutic agents. By exploring analogs Realizing that this treatment could pro- to thymidine for use as antiviral drugs, his vide great benefits to those struggling with research created a new scientific paradigm the growing HIV crisis in impoverished for antiviral drug development. Africa, Doctors Without Borders and Yale In the late 1950s, Bill synthesized one of students later lobbied Yale University and the first thymadine analogs, 5-iododeoxy- Bristol-Myers Squibb to make Zerit avail- uridine. At the time, it was thought to be able at a low cost for the African market. difficult to find antiviral drugs with a high Bill quickly joined the effort, even though therapeutic index, but Professor Herbert it meant a loss of personal income. ‘‘We E. Kaufman found that the compound are not doing this to make money, we are William H. Prusoff. Image credit: Laura Prusoff. could be used as an effective topical interested in developing a compound that doi:10.1371/journal.pbio.1001190.g001 treatment for herpes virus keratitis by would be a benefit to society,’’ he disrupting the virus’s ability to reproduce. explained. The effort to make Zerit more More significantly, though, this discovery affordable was a success: millions of people potential for using boronated-thymidine was a scientific game changer—it was the around the world benefited from Bill’s analogs as sensitizing cancer agents for first time that a clinical antiviral drug had research and humanitarian efforts. neutron therapy. been shown to have selective antiviral Bill was born on June 25, 1920, in New Bill’s remarkable contributions did not go activity if used properly. York City and attended the University of unnoticed in his lifetime. Among his many My association with Bill started in the Miami. After receiving his undergraduate accolades, he received the ASPET Award early 1970s during my postdoctoral work degree in chemistry, he obtained his PhD from the American Society of Pharmacology at Yale. Together with Professor David from Columbia University and later com- and Experimental Therapeutics and the Ward, we found that 59amino-5-iodode- pleted his postdoctoral training in the Peter Parker Medal, Yale School of Medi- oxyuridine had a high degree of selectivity laboratory of Professor Arnold Welch at cine’s highest award. He also received the against the herpes simplex virus in culture. Case Western Reserve University. After Inaugural Lifetime Achievement Award Around the same time, Dr. James Black Dr. Welch was recruited by Yale to head from the Yale Comprehensive Cancer and Dr. Gertrude Elion at Burroughs the Medical School’s pharmacology de- Center. His legacy was further solidified Wellcome found that acyclovir, another partment, Bill was invited to join the same when the School of Medicine established an nucleoside analog, also exhibited anti- department as an assistant professor and endowed chair in his name and the herpes virus behavior in culture. Scientif- was subsequently promoted to the rank of Department of Pharmacology named one ically, these were major breakthroughs professor. This relationship at Yale would of its conference rooms after him. In because these two discoveries were the first span over the next 58 years, with Bill addition, the International Society for Virus demonstrations of highly selective antiviral becoming one of Yale’s most well respect- Research established the William Prusoff drug behavior due to the unique proper- ed scientists and teachers. Young Investigator Lecture Award. ties of the herpes simplex virus. Subse- Though Bill officially retired at age 70, Despite his numerous awards and quently, it was found that the selectivity he never stopped working and continued prestigious accomplishments, Bill was an was due to the preferential activation of to be industrious. Until his death, his work extremely humble and down-to-earth man compounds by viral specified thymidine as professor emeritus concentrated on the who was quick to understate his achieve- kinase. Due to an unexpected toxicity found in young mice, 59amino-5-iodode- Citation: Cheng Y-C (2011) William H. Prusoff (1920–2011): Father of Antiviral Chemotherapy. PLoS Biol 9(11): oxyuridine was never further developed, e1001190. doi:10.1371/journal.pbio.1001190 but acyclovirin went on to become the first Published November 8, 2011 orally active anti-herpes virus drug. Copyright: ß 2011 Yung-Chi Cheng. This is an open-access article distributed under the terms of the In the 1980s, while the AIDS epidemic Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any was spreading and found to be caused by medium, provided the original author and source are credited. HIV, Bill and the late Dr. Tai-Shun Lin Competing Interests: The author has declared that no competing interests exist. discovered that a compound synthesized * E-mail: [email protected] PLoS Biology | www.plosbiology.org 1 November 2011 | Volume 9 | Issue 11 | e1001190 ments and even quicker to share the credit Foundation to support various programs, was. He even kept on sending us jokes with others. He lived modestly, unselfishly, including the United Way and the Yale through email when he couldn’t tell them and with the highest integrity. These traits Initiative for the Interdisciplinary Study of in person. made him an extremely popular and Anti-Semitism. He dedicated his life to the For those of us fortunate enough to highly respected individual everywhere. I service of others because he saw generosity have personally known him, we were do not remember a time that anyone and helping as a natural extension of the gifted with his peculiar sense of humor, would say anything bad about him. He human condition. He was a role model for warm welcoming company, and deep was always eager to assist others. As a scholars to follow. wisdom. Bill’s influence was much broad- fellow at Pierson College here at Yale, he Bill was always upbeat, smiling and er, though: training a new generation of would provide students with help but ready with a joke. His lifelong optimism in scientists who have gone on to become never boasted or took credit. Bill also the worst of times was always inspiring— successful in their own right, rippling with generously contributed to charities, en- he often said ‘‘the best is yet to come.’’ their own contributions that have affected dowing several lectureships in pharmacol- Even in the hospital under intense dis- others. For the millions of lives his work ogy, virology, and public health at Yale, comfort, he kept a lighthearted and has touched and saved, we have lost a supporting research in several laboratories, positive disposition, making light of his giant scientist in this age. and establishing the William H. Prusoff situation when we knew how serious it PLoS Biology | www.plosbiology.org 2 November 2011 | Volume 9 | Issue 11 | e1001190.