Assistant Professor, Department of Biochemistry
Broadly stated, the objective of our research is to understand principles governing molecular recognition by proteins and antibodies, with the long-term goal of developing new research tools and therapies. Students and post-doctoral fellows can expect to gain expertise in new and traditional biochemical techniques including phage display (library design, synthesis, and screening), protein expression and purification, structural analysis by circular dichroism and X-ray crystallography, and viral neutralization assays. We are currently engaged in two lines of research.
1. Antibody Recognition Explored by Phage Display. Antibody phage display has emerged as a powerful alternative to hybridoma technology for the generation of monoclonal antibodies and analysis of their interactions with antigens. It is now possible to select high-affinity antibodies against virtually any antigen from phage libraries that bear tailored diversity elements encoded by synthetic DNA ("synthetic antibodies"). This approach obviates the requirement for animal immunization, greatly reducing the labor and cost of antibody production. Selective enrichment of high-affinity binders from phage antibody libraries under controlled conditions enhances the reliability of output antibodies, and permits selection of binding with user-specified stringency. The expression of antibody domains on the surface of bacteriophage was first reported nearly two decades ago, but only recently have synthetic libraries (where diversity is not borne from natural source repertoires) become sophisticated enough for general use. We are developing and testing new synthetic antibody technologies to produce therapeutic, diagnostic, or research agents. Our strategy involves two aspects: first, we use high-throughput mutagenesis to interrogate physicochemical parameters of high-affinity antibody-antigen interactions; and second, we utilize the information obtained from these studies to engineer new synthetic libraries directed against targets that have resisted traditional antibody isolation methods.
2. Dissecting Mechanisms of Viral Membrane Fusion. The envelope glycoproteins of membrane-bound viruses such as HIV-1, influenza, and ebolavirus all catalyze viral entry into host cells using essentially the same mechanism. Central to this mechanism are well-timed conformational changes of the envelope glycoprotein that result in formation of a six-helix bundle hemifusion intermediate. Formation of this hemifusion intermediate provides the driving force for fusion of the virus and host cell membranes. Small molecules, peptides, or proteins that bind viral envelope glycoproteins and prevent formation of the hemifusion intermediate have been used clinically as antiviral therapies. In addition, antibodies arising from natural infection (or other sources) that prevent the formation of the hemifusion intermediate are able to effectively neutralize the virus, suggesting that conformational mimicry of viral glycoprotein in the prefusion states may serve as an avenue for vaccine development. Using synthetic antibody technologies coupled with traditional biophysical and biochemical approaches, we seek to understand details of the viral membrane fusion process and which steps along the pathway are susceptible to inhibition by antibodies. Information gained from these studies will pave the way for structure-based vaccine design.
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Albert Einstein College of Medicine
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