Engineered Protein Therapeutics
The current paradigm of drug development is to create single-function molecules that bind tightly to their targets and inhibit their function. In contrast, natural processes, including defense against pathogens and disease, involve many elements: multiple protein domains, weak interactions that function cooperatively, geometrically optimized elements, and so on. The spatial and quantitative aspects of such systems are tweaked during evolution to create defenses that do not resemble the simple molecules designed by humans. Our goal is to create complex therapeutic proteins and cells that mimic natural systems. We have engineered proteins that deliver an activating hormone or cytokine, either erythropoietin or interferon alpha, to specific target cells. The quantitative aspect is to mutate the cytokine and reduce its activity, so that cell binding is driven by an antibody element to which the cytokine is fused. The spatial aspect is primarily to use a linker that allows simultaneous binding of the cytokine and antibody elements to their receptors, and also maximizes the rate of cytokine binding after the antibody element has already bound.
Shapesifter: We have developed Shapesifter, a three-dimensional constrained Brownian dynamics (CBD) simulation system for modeling protein systems at the domain level of detail (“coarse-grained”), and shown its application to quantitatively engineered therapeutic proteins. The system focuses on a size scale below the resolution of the light microscope, where movement is difficult to observe and human intuition is poor, and above that of single atoms (the domain of more traditional molecular dynamics simulation). Shapesifter allows the representation and modeling of macromolecular systems including Brownian forces, volume exclusion, linkers of various stiffnesses/material properties, electrostatics, and association/dissociation interactions. We are interested in applications of this modeling approach to various engineered multidomain protein systems, including therapeutic protein fusions, in order to optimize their geometry and quantitative properties. Shapesifter is under ongoing development and is available to the synthetic biology community at http://shapesifter.org.
Robinson-Mosher A, Shinar T, Silver PA, Way J. (2013). Dynamics simulations for engineering macromolecular interactions. Chaos. 23(2), 025110. PMID: 23822508
Robinson-Mosher A, Chen JH, Way J, Silver PA. (2014). Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding. Biophys J. 107(10), 2456-66. PMID: 25418314
Burrill DR, Vernet A, Collins JJ, Silver PA, Way JC. (2016). A targeted erythropoietin that selectively stimulates red blood cell expansion in vivo. Proceedings of the National Academy of Sciences USA. PMID: 27114509
Researchers: Jungmin Lee and Nathan Rollins (graduate students)