MEMPHIS, Tenn., Jul. 9, 2021 /PRNewswire/ — Scientists and collaborators at St. Jude Children’s Research Hospital in Sweden and Japan report that the enzyme NUDT15 plays a role in how patients respond to antiviral therapy containing the common drugs ganciclovir and aciclovir . The researchers showed that NUDT15 status can help predict how individuals will respond to treatment for cytomegalovirus, a serious infection common in people undergoing bone marrow transplants. The article was published today in Nature Communications.
St. Jude scientists have expanded their work to evaluate how a particular enzyme affects the response to antiviral drugs.
“Our lab has long been interested in understanding why patients respond differently to nucleoside analogs. These molecules represent a large class of drugs widely used in anticancer and antiviral therapy,” said co-corresponding author Jun J. Yang, Ph. .D. , St. Jude Pharmaceutical Sciences and Oncology. “A few years ago, we discovered an enzyme called NUDT15 that metabolizes the leukemia drug thiopurine. We found genetic variants in the NUDT15 gene that accurately predict the risk of thiopurine toxicity. These genetic factors are now routinely used to individualize the way we give thiopurine.” “To leukemia patients to avoid side effects. Building on that, we wanted to know if drugs similar to thiopurine would also be affected by this enzyme, and we were quite surprised to see such a remarkable effect on these popular antiviral therapies.”
Looking for a similar backbone
Pharmaceutical compounds often consist of the same or a similar basic backbone. The researchers looked for drugs that have a similar chemical structure to thiopurine. The scientists listed such drugs and conducted experiments to determine whether those drugs were also metabolized by NUDT15. The work revealed that NUDT15 polymorphisms strongly influence the metabolism of the common antiviral drugs ganciclovir and aciclovir. These two drugs are widely used to treat infections such as cytomegalovirus and herpes simplex virus.
“These drugs are an important part of antiviral treatment for patients, such as those in St. Jude, who have compromised immune systems and cannot fight infection as easily,” says first author Rina Nishi, Ph.D., St. Jude. pharmaceutical. Sciences. “We have shown that NUDT15 can effectively inactivate these antiviral drugs.”
With colleagues in Sweden, led by co-corresponding author Pal Stenmark, Ph.D., Stockholm University and Lund University, the team recorded the crystal structures of the aciclovir metabolite bound to NUDT15. This allowed the researchers to better understand how the enzyme interacts and the ways it works differently compared to how NUDT15 affects thiopurine.
An international source gives an idea
NUDT15 deficiencies are more common in people of Asian descent. Together with colleagues in Japan, the team looked at patient data from Japan’s Bone Marrow Transplant Registry. Many patients in the registry had been treated with ganciclovir or acyclovir. The scientists found that patients with NUDT15 deficiency experienced better infection control because they had higher levels of the active form of the drugs in their system.
The research suggests that understanding NUDT15 status may be important in predicting how patients respond to these antiviral therapies.
“Infections are a serious complication for children with cancer undergoing bone marrow transplantation,” says co-corresponding author Motohiro Kato, MD, Ph.D., Children’s Cancer Center, National Center for Child Health and Development, Tokyo. “This new understanding of NUTD15 and how it affects the metabolism of antiviral drugs could potentially tailor therapy based on the NUDT15 genotype to improve efficacy and reduce toxicity.”
The other authors of the study are Takanori Mizuno and Yuji Yamada, Children’s Cancer Center, National Center for Child Health and Development, Tokyo; Daniel Rehling, Arrhenius Laboratories of Natural Sciences, Stockholm University; Tatsuo Ichinohe, Research Institute of Radiation Biology and Medicine, Hiroshima University; Makoto Onizuka, Tokai University School of Medicine; Yoshiko Atsuta, Japan Data Center for Hematopoietic Cell Transplantation; and Colton Smith, Brandi Clark, Xujie Zhao, Scott Brown, Brandon Smart, Takaya Moriyama, Lei Yang, Wenjian Yang, and Paul Thomas, all from St. Jude.
The study was funded by the National Institutes of Health (GM118578 and GM141947), the Agency for Medical Research and Development (20kk0305014), the Swedish Research Council (2018-03406), the Crafoord Foundation and the Swedish Cancer Society (201287), and ALSAC , St. Jude’s fundraising and awareness organization.
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital is a leader in how the world understands, treats and cures childhood cancer and other life-threatening diseases. It is the only National Cancer Institute-designated Comprehensive Cancer Center dedicated solely to children. Treatments developed in St. Jude have helped increase childhood cancer survival rates from 20% to 80% since the hospital opened more than 50 years ago. St. Jude freely shares the breakthroughs it makes, and every child saved in St. Jude means doctors and scientists around the world can use that knowledge to save thousands more children. Families never receive a bill from St. Jude for treatment, travel, housing and food – because the whole family should be concerned about helping their child. For more information, visit stjude.org or follow St. Jude on social media at @stjuderesearch.
SOURCE St. Jude Children’s Research Hospital