By  Jennifer McManamay
Chemical engineering Ph.D. student Zixian Cui and assistant professor of chemical engineering Rachel Letteri
A peptide synthesizer (foreground) is a key piece of equipment for chemical engineering assistant professor Rachel Letteri (right) and Ph.D. student Zixian Cui, shown working in Letteri’s polymer biomaterials Lab at the University of Virginia.

“Sorry I’m late,” Rachel Letteri said tuning into a Zoom call — hair still damp from a shower — to talk about an exciting new research grant from the National Institutes of Health.

“Someone in my running group dropped their keys, and we were retracing our steps to find them,” she said, before turning to how the NIH grant could help unlock the medicinal potential of peptides — protein fragments made of amino acids, which the body can use to fight everything from infection to stroke.

Letteri, an assistant professor in the University of Virginia Department of Chemical Engineering, runs regularly with colleagues, who include graduate students and faculty from UVA’s schools of Engineering and Applied Science and Medicine.

Those runs have led to ideas Letteri will explore through the grant, but the story also illustrates something crucial to her successful application for the NIH’s prestigious Maximizing Investigators’ Research Award for Early-Stage Investigators: The support and collegiality of the UVA research community.

The MIRA, as the grant is known, comes on the heels of another rising-star recognition for Letteri, the National Science Foundation CAREER Award. The MIRA is coveted because of its flexibility; the grant allows investigators to broaden their research scope within the mission of the National Institute of General Medical Sciences, without tying the research paths to a specifically funded project.

Portrait of Rachel Letteri
Rachel Letteri, assistant professor of chemical engineering, landed a $1.8 million National Institutes of Health MIRA.

Assistant professor Steven Caliari earned a MIRA in 2020, and his reviews of Letteri’s proposal were critical.

“Steven had such an important role in this, from encouraging me to apply to reviewing application drafts,” Letteri said. “So many others contributed as well — the chemical engineering department is really incredible. And the polymer research community is also amazing, willing to provide input and support my students. It definitely was not a one-person effort by any stretch of the imagination.”

Letteri’s polymer biomaterials lab will receive $1.8 million over the next five years, which includes financial support for graduate students.

“One of the most exciting things about this MIRA is I started with probably the best — not probably, I started with the best students I could have asked for — to build the lab,” said Letteri, who arrived at UVA in 2018. “The flexible funding gives all of these really awesome students an opportunity to explore and build a new, central direction in the lab.”

All true, but Letteri is too modest, said William Epling, chair of the department.

“Rachel is so curious and creative in her approach, the MIRA is perfect for her,” said Epling, the Alice M. and Guy A. Wilson Professor of Chemical Engineering. “Biomaterials and tissue engineering have emerged as research areas where UVA is having an impact, and Rachel is a big part of that. There’s a lot of energy and excitement underlying their important work. For our department to get two MIRA awards in two years tells me others see that too.”

Letteri’s team members on the MIRA — Ph.D. students Mara Kuenen, Zixian Cui, Mark Bannon and Vince Gray — will focus on how to use the powerful chemistry of polymers to overcome the limitations of peptides as treatments in health care. Her lab specializes in biomaterials combining peptides with polymers to endow materials with new functions useful in engineering and medicine.

Polymers, sometimes called macromolecules, are any material composed of large molecules that are themselves made of repeating subunits, like building blocks. Those blocks and the chemical bonds between them can be altered in tiny ways that result in big changes to the material’s physical properties, such as whether it’s hard or soft, elastic or liquid, and how quickly it dissolves.

The design possibilities are endless, which is why both natural and manmade polymers are everywhere. They’re in food, clothing, plastics — and the clear, water-absorbing gels Letteri engineers in her lab to mimic living tissue. With the MIRA, she will also develop new therapeutic formulations.

The specific application of polymers to peptide therapeutics wasn’t in Letteri’s plans until she met Dr. Molly Hughes, a professor at the medical school’s Division of Infectious Diseases and International Health.

Hughes’ team was investigating immune-system peptides as new antibiotics against numerous multi-drug-resistant bacteria. They were looking for a collaborator familiar with peptide chemistry.

“I was ecstatic to receive a note from Professor Shayn Peirce-Cottler in biomedical engineering connecting me with Molly and her lab in my first couple weeks at UVA. The potential to advance medicine is why I got into research to begin with, and the opportunity to work in step with a clinician was incredibly exciting,” Letteri said, noting how important it is for engineers and researchers to calibrate their work to real-world needs that medical practitioners are exposed to every day.

Despite promising lab studies, few peptide therapeutics have made it past clinical tests because of various limitations.

“Peptides can be quite powerful as therapeutics for a range of conditions,” Letteri said. “The problem is they don’t last long in the bloodstream because they’re so small, or they’re cleared by the immune system. They can also be toxic to healthy cells, or may not be completely soluble.”

Enter the polymers.

“The goal of the MIRA project is to use polymers to present these therapeutic peptides in ways that help to maximize how they work,” Letteri said. “We need to pin down what molecular-level details really make these peptides shine as therapeutics.”

Potential presentations include attaching multiple peptides to a single polymer chain so they can work together or by encapsulating peptides within a polymer carrier to slowly make them available.

For example, to treat infection, attaching an antimicrobial peptide to a water-soluble polymer reduces toxicity and stabilizes the peptide in the presence of enzymes that degrade peptides — but doing so also blocks interaction with the bacteria the peptide is meant to kill.

What if you rearrange the polymer’s building blocks?

“We think water-soluble polymers have tremendous potential in displaying peptides in different ways, and we have a lot of tunability over how we build these molecules,” Letteri said.

Letteri also began working with Dr. William Petri, chief of UVA’s infectious diseases division, whose lab was getting excited about a peptide that may be helpful for treating COVID-19.

Petri, the Wade Hampton Frost Professor of Medicine, is one of Letteri’s running buddies. Readers might recognize him as the UVA physician who answers questions about COVID-19 for the local newspaper.

“Since this peptide also doesn’t last long in the body, we thought this could be a really nice project to team up on and see if we can help extend the life of those peptides,” Letteri said.

A seed grant from the UVA Global Infectious Disease Institute funded early work with Hughes’ lab in combining polymers with antimicrobial peptides, while another from the Center for Engineering in Medicine funded her collaboration with Petri.

“The internal UVA sources helped jumpstart my lab’s efforts to use polymers to present and maximize function of therapeutic peptides with Molly and Bill,” Letteri said. “This MIRA will really launch this as a long-term research direction in my lab, which I’m excited about.”

Letteri’s MIRA will fund the development of polymers for attachment and encapsulation of peptide therapeutics to treat infections caused by viruses and resistant bacteria as well as peptides with the potential to treat malformed proteins associated with diseases such as Amyotrophic Lateral Sclerosis and Alzheimer’s.

The research has broader implications, too, because peptides also appear to be effective against injury resulting from heart attack, stroke and radiation.

“Hopefully what we learn about how molecular structure relates to properties, and ultimately the function of peptides as therapeutics, will help others working in the same area and thereby accelerate the rollout of this exciting class of therapeutics,” Letteri said.

That matters to Letteri, for whom collaboration, teaching, and learning within the science community is so important.

This doesn’t mean she isn’t competitive, though. All that running?

Letteri led the University of Virginia Department of Chemical Engineering 2021 Olympic Games gold medal-winning team. There’s even a podium shot to prove it.

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