Developing synthetic protein therapeutics

The majority of receptors on the inside and outside of diseased cells are largely "undruggable" by current therapies, which overwhelming are small molecule drugs. However, by manipulating the structure and function of proteins, researchers can develop synthetic proteins as modulators of disease-relevant cell function and fate. Dr. Brian McNaughton, of Colorado State University, is focused on utilizing proteins as basic research tools and therapeutic leads. His interests have led him to develop synthetic proteins capable of modulating disease-relevant receptors and cellular processes, with an emphasis on macromolecular targets that present a challenge to traditional small molecule drug discovery. In doing so, Dr. McNaughton's research team has expanded the functional diversity of proteins as basic research tools and therapeutic leads with the potential to improve human health.

Dr. McNaughton's research has established a fundamentally new paradigm in drug discovery, which rests on his team's ability to engineer or evolve synthetic proteins with therapeutic application, as well as develop nanomaterials for targeted delivery of protein drugs to diseased cells. Research in the McNaughton lab spans basic science and translational research - the discovery of new drug leads and initial assessments of these reagents in living human cells and in living systems. His research may lead to a dramatic increase in the number of protein-based drugs for numerous cancers and infections diseases, including HIV and Ebola. In fact, his previous research has received over $2.1 million in grant funding for prostate cancer, leukemia, and HIV-related research. In short, the innovative paradigm shift in drug development posed by Dr. McNaughton and his team may one day provide therapeutic treatments that can only be imagined at present.

Current research includes:

  • Developing synthetic protein therapeutics to drug "undruggable" protein targets: Dr. McNaughton's team develops proteins as drugs that target cellular receptors that lead to disease, and confound traditional drug (small molecule centered) drug discovery. Diseases for which protein drugs are being generated include: HIV, Ebola, breast cancer, liver cancer, prostate cancer and leukemia.

  • Synthetic proteins that sequester disease-causing RNA: Dr. McNaughton's team targets disease-causing RNAs that are involved in multiple cancers, and infectious diseases like HIV. These RNA targets, and the synthetic proteins that regulate them, represent a new paradigm in drug discovery.

  • Developing nanomaterials for targeted protein drug delivery to diseased cells: Dr. McNaughton and his team develop nanomaterials for: (1) targeted delivery of proteins to diseased cells, and (2) sensing diseased cells in a complex environment. Much of Dr. McNaughton's research thus far with nanomaterials has been focused on prostate cancer.

Bio

Dr. Brian McNaughton began researching because he fell in love with the idea of using his imagination and creativity to develop new tools and resources with the potential to improve human health. The research conducted in his lab is fundamentally based on the following observation: the overwhelming majority of disease-causing receptors inside diseased cells are largely "undruggable" by current therapies. In order to modulate these receptors--and in doing so modulate disease-relevant cell function and fate--new paradigms must be established. Dr. McNaughton and his team are developing those new paradigms. Dr. McNaughton explains that while an undergraduate, he originally intended to study to be a medical doctor but later found that research was the most effective way for him to have an impact on the health of his community. He continues to conduct his research because of the scientific rigor required and also the impact he sees his research having on those affected by cancers or diseases, including some of his own family members. Dr. McNaughton's lab is currently a team of five graduate students and four undergraduate researchers. A typical Ph.D. in the McNaughton lab spans basic and translational research. For example, researchers typically start by using tools in chemistry and molecular biology to develop proteins with unique therapeutic potential. The ability of these new proteins to alter disease-relevant function is then tested outside and inside of living cells. Finally, students take new therapeutic proteins into early clinical trials, testing their toxicity, and utility to modulate disease in living systems (mice). The application of new protein therapeutics they develop typically target cancers and infectious disease.

Outside of research, in his free time, Dr. McNaughton enjoys collecting and tasting new wines and hiking. In addition, he loves to spend time with his family who keep him busy outside of his lab.

Website: http://sites.chem.colostate.edu/mcnaughtonlab/

Publications

Synthetic Proteins Potently and Selectively Bind the Oncoprotein Gankyrin, Modulate Its Interaction with S6 ATPase, and...

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Characterization of the Binding Interaction Between the Oncoprotein Gankyrin and a Grafted S6 ATPase

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Resurfaced Shape-Complementary Proteins That Selectively Bind the Oncoprotein Gankyrin

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Engineered M13 Bacteriophage Nanocarriers for Intracellular Delivery of Exogenous Proteins to Human Prostate Cancer Cells

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Synthetic RNA Recognition Motif Proteins that Selectively Recognize HIV-1 Trans-Activation Response Element Hairpin RNA

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Mutagenesis Modulates the Uptake Efficiency, Cell-Selectivity, and Functional Enzyme Delivery of a Protein Transduction Domain

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Awards

Leukemia Research Foundation Floyd A. Schlossberg Award, 2012-2013

Colorado State University

DoD-CDMRP Prostate Cancer Program New Investigator Award, 2010-2013

Colorado State University

Howard Hughes Medical Institute Post-Doctoral Fellow, 2007-2009

Harvard University

Robert and Marian Flaherty DeRight Fellow, 2002

University of Rochester

Patents

PCT/US2009/041984: "Supercharged proteins for cell penetration."

David R. Liu, Brian R. McNaughton, James J. Cronican, David B. Thompson. US Patent Application, filed June 10, 2010.

PCT/US2008/058716: "Small molecule modulators of melanin production."

Brian R. McNaughton, Peter Gareiss, Benjamin L. Miller, Glynis Scott. US Patent Application, filed November 27, 2008.

US20100266677 A1.: "Nucleic acid binding compounds and methods of use."

Benjamin L. Miller, Brian R. McNaughton, Peter C. Gareiss, Joseph Wedekind, Charles Thornton, Krysztof Sobczak. US Patent Application, filed July 28, 2008.

WO 2013/177201 A2.: "Detection of Biopolymer Interactions, Cancer Cells, and Pathogens Using Split-Supercharged GFP."

Brett D. Blakeley, Alex M. Chapman, Brian R. McNaughton. US Patent Application, filed November 28, 2013.

US14/088,81: "Multifunctional Bacteriophage for Delivery of Therapeutic and Imaging Proteinaceous Reagents."

Sandra M. DePorter, Irene Lui, Virginia J. Bruce, Brian R. McNaughton. US Patent Application, filed November 22, 2013.