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Liberty Blue Customer Highlight: Dr. Stephen E. Miller

December 15, 2019

CEM recently had the opportunity to interview Dr. Stephen E. Miller, a current postdoc in the Schneider lab at the National Cancer Institute (NCI). Dr. Joel P. Schneider started his career working with peptides while a graduate student at Texas A&M in the lab of Dr. Jeffery W. Kelly (now at Scripps). Dr. Schneider then performed postdoctoral work at the University of Pennsylvania with Dr. William F. DeGrado (now at UCSF). Dr. Miller began working with peptides during his graduate studies with Dr. Paramjit S. Arora at New York University. Dr. Miller is the lead author on a recent Schneider lab publication in ACS Central Science where they use one of their peptide hydrogels to control protein delivery.

Q: Could you provide some background on the Schneider research group?
The Schneider lab started at the University of Delaware in 2000. The lab has worked on a variety of projects within peptide science throughout the years but is best known for developing a class of self-assembling beta-hairpin peptides that form hydrogels. These materials form highly homogenous and reproducible fibrous networks that can be used for a variety of biomedical applications. In 2009, the lab moved to the US National Cancer Institute in Frederick, MD. Here, the lab has been able to take advantage of the extensive network of NCI scientists working at the cutting edge of cancer research, which has inspired the development new materials and drug delivery modalities.

Using a terminal interaction domain (ID) to control protein release from peptide hydrogel
1. Protein with ID: tunable release - longer IDs have slower release
2. Unmodified Protein: fast release
Q: What are your key research goals?
With respect to the peptide hydrogel projects, research efforts are split between two general areas. The first involves investigating the peptide self-assembly process or elucidating the molecular structure of the self-assembled fibers. In addition to expanding our understanding of these materials, such work could also provide insight to improve the rational design of new hydrogel materials. The other area of research utilizes hydrogels for different biomedical applications, such as for antibacterial, tissue regenerative, or drug delivery purposes. In efforts to improve protein drug delivery, we recently reported a new delivery strategy using one of our peptide hydrogels. Protein drugs often require frequent administration for efficacy, which can increase the cost of treatment and reduce patient compliance. We sought to create a highly tunable system, where the rate of drug release from a single administration could be easily controlled to fit a desired therapeutic timeline, and that could be easily applied to many different proteins. We accomplished this by installing a small interaction domain onto the terminus of a protein. This domain binds to the hydrogel network and its composition could be modified to alter drug release. The strategy can be easily applied to different proteins, including the human cytokine interferon-α. Using the red fluorescent protein mRuby3, we also show that this system can work in vivo, with a single administration of protein-loaded gel providing sustained delivery of protein for up to three weeks. We anticipate that this new approach can streamline future drug delivery efforts using our hydrogels.

Q: How has the Liberty Blue improved your research to date?
Due to many beta-branched residues and an unnatural D-proline, synthesizing our self-assembling peptides can be challenging. We previously used an automated peptide synthesizer with conventional conditions that required many double coupling steps. Although we could get good yields, it took two days to synthesize one sequence and the process created a large amount of solvent waste. We worked closely with chemists at CEM to develop specialized Liberty Blue conditions that could make even our most challenging sequences in a fraction of the time while reducing the amount of solvent needed. We’re extremely satisfied with our Liberty Blue because the faster synthesis process allows us to perform our desired experiments sooner.

Q: Do you think the Liberty Blue could be useful to other scientists?
We think the Liberty Blue would definitely be a useful tool for other researchers. For simple peptides, it’s easy to generate small libraries in a short amount of time. With minor optimization of the synthesis conditions, more challenging peptides can also be readily made.

For a selection of relevant publications from the Schneider lab, see:
Miller, S.E.; Yamada, Y.; Patel, N.; Suárez, E.; Andrews, C.; Tau, S.; Luke, B.T.; Cachau, R.E.; Schneider, J.P. ACS Cent. Sci. 2019, 5, 1750.
Yamada, Y.; Patel, N.L.; Kalen, J.D.; Schneider, J.P. ACS Appl. Mater. Interfaces. 2019, 11, 34688.
Nagy-Smith, K.; Moore, E.; Schneider, J.; Tycko, R. Proc. Natl. Acad. Sci. U.S.A. 2015, 112, 9816.