Dr. John Wai Speaks at BMC About Creating an Anti-HIV Drug

By Emma Nelson, Staff Writer

On Friday, September 30th, Dr. John Wai of WuXi Apptec (formerly Merck & Co.) spoke in the Park Science Building on Bryn Mawr’s campus. He was introduced by Professor Malachowski, who is standing in as chair of the Chemistry department. Malachowski was warm, and explained that he knew Dr. Wai through Wai’s wife, whom he had met many years ago while collaborating on research. Malachowski continued to give the audience of several dozen people a brief background on Dr. Wai.

Wai has studied at the University of Hong Kong and the University of British Columbia, and completed post-doctoral work at the Massachusetts Institute of Technology. He has worked at Merck & Co., a pharmaceutical company, for many years. During his distinguished career, Dr. Wai and his colleagues have been awarded the Prix Galien and ACS Heroes of Chemistry Awards for their work on Isentress™, an anti-HIV drug.

After the introduction, Dr. Wai himself stepped up and began his presentation, entitled “Discovery of HIV Integrase Inhibitors: From Diketoacid Hit to Raltegravir and Beyond.” He started by talking about the situation in 1997, when he and his team commenced their research. HIV/AIDS was an epidemic, he explained, showcasing World Health Organization global estimates on annual deaths at the time. There were few treatment options available, no vaccines, and incomplete structural information from which to base their research. This, Wai explained, made the first steps along their path to developing Isentress™ very difficult.

Academic papers on HIV-1 integrase (the part of the virus which attaches to host DNA and infects the host for life) concluded that it was “undruggable,” that it would be impossible to stop a person from being infected once exposed. However, Wai and his team persisted with their research. A major help to their efforts was collaboration with other scientists who were also working on the problem of inhibiting HIV integrase. This problem is that HIV is a stoichiometric enzyme. A “stoichiometric enzyme” refers to a particular atypical property of HIV: it can only do its job (infecting the host) once. If it is prevented, the virus becomes useless.

With this additional information, Wai and his team moved along with the early stages of drug development. In fact, they moved into Pre-Clinical Research, an important step on the way toward clinical animal and human trial, with only one “lead,” or prototype, instead of the typical two or more. This quickly transformed into clinical testing on animals: first rats, then eventually dogs and rhesus monkeys.

First results from the testing on rats went so well, Wai explained in good humor, that his team had a party in celebration. However, Wai grew serious as he continued. By the end of the week, no more than five days after the unbelievable news about their lead’s success, Wai was called and told that the dogs, in the second stage of clinical trials, had grown so sick that they had to be put down. Changes had to be made in certain properties of the chemical to make it safer, and with the determination of Wai and his colleagues, the lead was soon improved.

To explain the clinical trials on human patients, Wai presented an anecdote about his friend Skip, a man with HIV. Wai’s lead moved into human testing, but Skip was not able to join the clinical trials, due to his triple-class resistance, a certain state which is characterized by resistance to different types of antiretroviral drugs. Knowing that this was the case for many patients who desperately needed the drugs provided in clinical trials, Merck & Co. took a risk to get unqualified patients the prototype drug. However, this risk paid off for Wai’s friend Skip, whose HIV was undetectable for the first time in 20 years.

“I couldn’t hold back tears … no award is better than this,” Wai remembered thinking the first time he saw the newly-healthy Skip.

Dr. Wai finished his presentation with an overview of research done to prevent mutations of the HIV virus from halting or impairing the potency and efficacy of his new drug. Using three-dimensional computer models of his team’s prototype, Wai showcased one thing he could not understand: a feature of the molecular structure that should not have helped the drug work. If someone had told him to design the prototype like this, he explained, he would have called them wrong. Despite this inexplicable quirk, Isentress™ was approved by the FDA in 2007, as it passed through the human clinical trials and completed FDA review and monitoring successfully. Wai concluded that it took a lot of work- two decade’s worth, on his part- and luck to develop this drug from start to finish.

From the print edition published on Oct. 5, 2016

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