Just like medicinal chemistry, which shaped drug discovery in the 20th century, the field of protein therapeutics is positioned to lead drug discovery in the 21st century. A key strength of proteins as therapeutics is the ability to serve a highly specific and complex set of functions that cannot be mimicked by simple chemical compounds. Since the first recombinant protein therapeutic – human insulin – was introduced over 30 years ago, protein therapeutics have assumed a significant role in medicine.
The Chen Medicinal Protein Lab aims to accelerate the discovery, development and clinical translation of protein therapeutics through innovative protein engineering research. We believe that better medicine enables a higher quality of living, and protein engineers are charged to create the better medicine for today and tomorrow. We are particularly interested in the creation and engineering of affordable protein therapeutics to prevent and treat infectious diseases.
We draw talents from diverse fields ranging from medicine and biology to chemistry and engineering, and integrate tools from genetics, virology, immunology and imaging fields in order to create and engineer proteins for therapeutic application. Three projects currently under active investigation are 1) the creation of broadly neutralizing non-antibody proteins for combating bacterial infection, 2) the reprogramming of lentiviruses as vectors for disease-specific delivery of genetic payloads, and 3) the development of protein-based 3D materials for tissue engineering.
Non-antibody proteins for treating bacterial infection
Antibacterial resistance is a global public health crisis. Although many factors contribute to the emergence of antibiotic-resistant bacteria, the overuse of antibiotics in humans and veterinary medicine is believed to be a major contributing factor. Traditional antibiotics target one or more essential cellular pathways, providing a selective pressure for the emergence of bacterial variants that are able to evade the action of the antibiotic, thus perpetuating the problem of antibiotic resistance. An alternative approach to addressing the problem of bacterial infection is to neutralize a bacterium’s virulence factor(s). This approach can relieve the symptoms of infection without exerting a selective pressure for escape mutants, providing time for the host immune response to naturally clear the pathogen.
This project aims to create non-antibody protein neutralizers of secreted bacterial toxins to combat bacterial infection. We employ a designed ankyrin repeat protein as a scaffold for these studies primarily because of its ease of expression in and purification from E. coli, high thermostability and low immunogenicity. We envision that ankyrin protein-based toxin-neutralizers could potentially be delivered orally or intravenously to directly neutralize bacterial toxins in the intestine or in circulation. Currently, we are engineering neutralizers of toxins secreted by Clostridium difficile and Shiga toxin-producing E. coli.
Reprogramming lentiviruses for gene therapy
Gene therapy enables the correction of genetic anomalies in diseased cells and promises to provide a solution for inherit and acquired diseases, but a method for robustly programming vectors to deliver therapeutic gene cargo specifically and efficiently to diseased cells does not currently exist. Proteins that specifically bind markers on certain cell types, primarily monoclonal antibodies, already exist in abundance but there is currently no reproducibly effective way to functionalize viral vectors with these proteins. In the case of antibodies, non-covalent approaches to incorporate cell-binding proteins onto the lentivirus surface leaves the linkage vulnerable to interference from serum immunoglobulins in immune-competent individuals. The overall goals of this research theme are to i) enable facile reprogramming of lentivirus to deliver genetic payloads to specific cell types through covalent functionalization of lentiviruses in vitro with cell-binding proteins, and ii) enable the in vitro tuning of lentiviral vectors to minimize undesirable off-target gene transduction effects.
Protein-based 3D materials
Cells in tissues reside in a complex and dynamic extracellular matrix (ECM) where their role in tissue homeostasis, wound repair, and even pathophysiological events are regulated by a myriad of biophysical and biochemical cues. Synthesis of a material able to faithfully mimic the natural ECM represents the holy grail of tissue engineering. Recently, protein-based hydrogels have emerged as a promising alternative to synthetic polymer-based hydrogels for biomedical applications because proteins are naturally biocompatible, biodegradable and are able to better mimic the natural ECM. Our goal is to employ innovative protein engineering approaches to create a synthetic ECM composed entirely of functional proteins. In addition to providing a physical support for cell attachment and proliferation, hydrogel matrix needs to be highly porous to allow diffusion of nutrient into cells encapsulated within the matrix.