Molecular Musical Chairs

The human papillomavirus (HPV) vaccine is safe and effective – but it’s not for everyone.

“Some people can’t be vaccinated,” says Michelle Ozbun, PhD. “They don’t have access to the vaccine, they can’t afford it or they can’t be vaccinated.”

According to the Centers for Disease Control and Prevention, HPV accounts for more than 90% of cervical cancers, more than 90% of anal cancers and a significant percent of other types of cancers.

Ozbun, a professor of Molecular Genetics & Microbiology and of Obstetrics & Gynecology at The University of New Mexico, conducts HPV research at the UNM Comprehensive Cancer Center.

She and her team published a research article earlier this year in Antimicrobial Agents and Chemotherapy in which they describe how a drug called protamine sulfate blocks HPV infection. Like a game of musical chairs among molecules, the drug molecules bind to heparan sulfate cell receptors, preventing HPV virus particles from doing so.

“The [HPV] virus has a net charge,” Ozbun says, “and the heparan sulfate cell receptor has a net charge. They attract one another. That’s what the virus uses to attach to cells.”

Once attached to the cell surface, a HPV particle can enter the cell and co-opt its molecular machinery to make more copies of itself. But if protamine sulfate molecules bind to the heparan sulfate cell receptors instead, HPV particles have nothing to attach to and the infectious process stalls.

Ozbun and her team reported that protamine sulfate not only prevents HPV infection but also reduces the risk of infection even after cells have been exposed to the virus. The team carried out their studies in lab experiments and in mice. The next step is to test the drug for this new use in people.

New drugs go through a decade or more of testing in people before receiving approval from the U.S. Food and Drug Administration (FDA), but once a drug has FDA approval, getting approval for a different use simply requires efficacy testing for the new use.

Protamine sulfate has had FDA approval for decades. Given intravenously, it counteracts a blood-thinning medication called heparin, which is often given to people before surgery to avoid complications during a procedure. After surgery, protamine sulfate is injected to restore the blood’s life-saving ability to clot.

The Ozbun team, inspired by the ideas of teammate Zurab Surviladze, PhD, knew that in blood, protamine sulfate blocks heparin by binding to heparan sulfate cell receptors. They designed studies to show that protamine sulfate could also bind to heparan sulfate cell receptors when applied topically.

They also found that protamine sulfate protects against all strains of HPV (the current HPV vaccine only protects against the nine most prevalent HPV types). And surprisingly, the team found that even after a cell had been exposed to HPV, protamine sulfate could keep the virus from taking over the cell and making more copies of itself.

“‘Infected’ means that the virus is already inside the cell and is starting to replicate,” Ozbun explains. “‘Exposed’ just means that the virus has come in contact with a cell that might take it up, but you can still block the virus from getting in and starting an infection.”

Ozbun wants to translate this discovery into something people can soon use.

“We talk about reducing risk,” Ozbun says of HPV infection. “One of the things that’s important to me is the possibility of getting it [protamine sulfate] into something that’s affordable.”

She and her team will study how protective protamine sulfate is when combined with hyaluronic acid, a common ingredient in skin moisturizers and sexual lubricants. Moisturizers and lubricants are cheaper than vaccines, and Ozbun hopes they can be a good way to reduce the risk of infection.

“You have to come up with something that’s really good and that people will use,” Ozbun says. She and her team may have discovered that something.

About Michelle Ozbun, PhD

Michelle Ozbun, PhD, is a professor in the UNM departments of Obstetrics & Gynecology and Molecular Genetics & Microbiology. She is The Maralyn S. Budke Endowed Professor in Viral Oncology and co-leads the Cellular and Molecular Oncology Research Program at the UNM Comprehensive Cancer Center.

Paper Reference       

“Protamine Sulfate Is a Potent Inhibitor of Human Papillomavirus Infection In Vitro and In Vivo” was published online on January 18, 2022, in Antimicrobial Agents and Chemotherapy (https://journals.asm.org/journal/aac). Authors are Jesse M. Young, Amira Zine El Abidine, Ricardo A. Gómez-Martinez, Virginie Bondu, Rosa T. Sterk, Zurab Surviladze, and Michelle A. Ozbun.

About the UNM Comprehensive Cancer Center

The University of New Mexico Comprehensive Cancer Center is the Official Cancer Center of New Mexico and the only National Cancer Institute-designated Cancer Center in a 500-mile radius. Its more than 120 board-certified oncology specialty physicians include cancer surgeons in every specialty (abdominal, thoracic, bone and soft tissue, neurosurgery, genitourinary, gynecology, and head and neck cancers), adult and pediatric hematologists/medical oncologists, gynecologic oncologists, and radiation oncologists. They, along with more than 600 other cancer healthcare professionals (nurses, pharmacists, nutritionists, navigators, psychologists and social workers), provide treatment to 65% of New Mexico’s cancer patients from all across the state and partner with community health systems statewide to provide cancer care closer to home. They treated approximately 14,000 patients in about 100,000 ambulatory clinic visits in addition to in-patient hospitalizations at UNM Hospital. A total of nearly 400 patients participated in cancer clinical trials testing new cancer treatments that include tests of novel cancer prevention strategies and cancer genome sequencing. The more than 100 cancer research scientists affiliated with the UNMCCC were awarded $35.7 million in federal and private grants and contracts for cancer research projects. Since 2015, they have published nearly 1000 manuscripts, and promoting economic development, they filed 136 new patents and launched 10 new biotechnology start-up companies. Finally, the physicians, scientists and staff have provided education and training experiences to more than 500 high school, undergraduate, graduate, and postdoctoral fellowship students in cancer research and cancer health care delivery. Learn more at unmhealth.org/cancer.