This is a guest editorial by Wenshe Ray Liu, a chemistry professor at Texas A&M University.
It was midnight on Oct. 29, 2014. After submitting a National Science Foundation proposal, I took a shower to soothe my exhaustion. While rubbing the left side of my neck, I felt an eerily large lump. I visited my family doctor, who carefully examined the lump and determined that it could be one of two things, a lymph node that had swollen from infection—or a tumor. He put me on amoxicillin for a month. The lump grew.
A biopsy confirmed my worst fears: I had aggressive tumorigenesis. After a transfer to the MD Anderson Cancer Center, I was diagnosed with stage IVB nasopharyngeal cancer. The tumor had pressed up onto the left trigeminal nerve, which explained the bothersome uncontrollable saliva secretion that had been plaguing me. The cancer had locally metastasized to both sides of the neck. Without treatment, I was given only a year.
I was put on chemotherapy and radiation right away. Each chemo infusion left me bedridden and sweating profusely for a week. My sense of taste disappeared, followed by sudden hair loss. My wife, Wei, worried that I would lose so much weight and need a feeding tube. So, for as long as I was able to get up from bed, Wei encouraged me to take long walks around the community park. It was during these walks that we talked about a lot of things, including some tough problems in my research.
A year before my diagnosis, my research group published a technique that used an enzyme to activate the C terminal end of ubiquitin, a human regulatory protein, for conjugation with an amine. Although the technique can be extended to some ubiquitin-like proteins, it cannot be generalized to all proteins. I struggled to come up with an idea that could chemically conjugate a protein with an amine as a C-terminal amide. I constantly complained how tricky a protein-involved chemical reaction could be until Wei suggested checking old-school reactions that hydrolyzed proteins. This suggestion immediately reminded me of the protein cyanylation at cysteine for cysteine mapping. I had read about using this reaction to soften wool in Australia, which left me with a strong memory of the process. I asked my graduate student Xiaoyan Wang to test the idea by adding a cyanylating reagent and glycine simultaneously to a G76C mutant of ubiquitin. The result was striking. Glycine replaced cysteine in almost all detected ubiquitin. Xiaoyan also tested several different amines. They all worked very well. I was excited to name the reaction “activated cysteine-based protein ligation” (ACPL).
Xiaoyan graduated in August 2015, and I finished my treatment around the same time. I was still confined to my bed because of the severe pain caused by radiation, and my throat had swollen to a point where only liquid could pass. I dropped 20 pounds in August alone. Wei persuaded me to give up doing research. With my life in limbo, I sadly agreed.
I was on the verge of permanently dissolving my group in the fall of 2016 when I received a grant from the US National Institutes of Health for my research. With reasonably recovered health and the new funding, my passion for science rose from the ashes.
Over the next few years, my research group accomplished a thorough characterization of the ACPL reaction, demonstrating its vast versatility in different reaction conditions and in making a variety of protein conjugates. Our work is helping to energize the already vibrant field of protein ligation research.
When COVID-19 emerged, I knew from my experience as a cancer patient that the pandemic would turn our lives upside down. I quickly diverted my group to work on COVID-19 drug discovery, and we have developed several potent anti-SARS-CoV-2 small molecules.
For many chemistry colleagues who have been confined at home due to COVID-19, I would like to share some optimism. My experience with cancer has shown me that we should never lose hope no matter how dire a situation is. This, too, shall pass.
Views expressed on this page are those of the author and not necessarily those of ACS or C&EN.