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Faculty Profile

Jonathan R. Lai, Ph.D.

Dr. Jonathan R. Lai

Associate Professor, Department of Biochemistry


Professional Interests

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.


Selected Publications

 Selected Publications

Chen, G.; Koellhoffer, J. F.; Zak, S. E.; Frei, J. C.; Liu, N.; Long, H.; Ye, W.; Nagar, K.; Pan, G.; Chandran, K.; Dye, J. M.*; Sidhu, S. S.*; Lai, J. R.*  Synthetic Antibodies with a Human Framework that Protect Mice from Lethal Sudan Ebolavirus Challenge.  Submitted.

Higgins, C. D.; Malashkevich, V. N.; Almo, S. C.; Lai, J. R.* Influence of a Heptad Repeat Stutter on the pH-Dependent Conformational Behavior of the Central Coiled-Coil from Influenza Hemagglutinin HA2. Proteins.In press.

Koellhoffer, J. F.; Dai, Z.; Malashkevich, V. N.; Stenglein, M. D.; Liu, Y.; Toro, R.; Harrison, J. S.; Chandran, K.; DeRisi, J. L.; Almo, S. C.; Lai, J. R.*  Structural Characterization of the Glycoprotein GP2 Core Domain from the CAS Virus, a Novel Arenavirus-like Species. J. Mol. Biol., 2014, 426, 1452-1468.

Koellhoffer, J. F.; Higgins, C. D.; Lai, J. R.*  Protein Engineering Strategies for the Development of Viral Vaccines and Immunotherapeutics. FEBS Lett., 2014, 588, 298-307.

Liu, Y.; Higgins, C. D.; Overstreet, C. M.; Rai, K. R.; Chiorazzi, N.*; Lai, J. R.*   Peptides that Bind Specifically to an Antibody form a Chronic Lymphocytic Leukemia Clone Expressing Unmutated Immunoglobulin Variable Region Genes.  Mol. Med., 2013, 19, 245-252.

Higgins, C. D.; Koellhoffer, J. F.; Chandran, K.; Lai, J. R.*  C-Peptide Inhibitors of Ebola Virus Glycoprotein-Mediated Cell Entry: Effects of Conjugation to Cholesterol and Side Chain-Side Chain Crosslinking  Bioorg. Med. Chem. Lett., 2013, 23, 5356-5360.

Harrison, J. S.*; Higgins, C. D.; O’Meara, M. J.; Koellhoffer, J. F.; Kuhlman, B. A.; Lai, J. R.*  Role of Electrostatic Repulsion in Controlling pH-Dependent Conformational Changes of Viral Fusion Proteins  Structure, 2013, 21, 1085-1096.

Regula, L. K.; Harris, R.; Wang, F.; Higgins, C. D.; Koellhoffer, J. F.; Zhao, Y.; Chandran, K.; Gao, J.; Girvin, M. E.; Lai, J. R.* Conformational Behavior of Peptides Corresponding to the Ebolavirus GP2 Membrane-Proximal External Region in the Presence of Micelle-Forming Surfactants and Lipids. Biochemistry, 2013, 52, 3393-3404.

Stewart, A.; Harrison, J. S.; Regula, L. K.; Lai, J. R.*  Side Chain Requirements for Affinity and Specificity in D5, an HIV-1 Antibody Derived from the VH1-69 Germline Segment.  BMC Biochemistry, 2013, 14, 9.

Koellhoffer, J. K.; Chen, G.; Sandesara, R.G.; Bale, S.; Saphire, E. O.; Chandran, K.*; Sidhu, S. S.*; Lai, J. R.*  Two Synthetic Antibodies that Recognize and Neutralize Distinct Proteolytic Forms of the Ebola Virus Glycoprotein. ChemBioChem, 2012, 13, 2549–2557.

Koellhoffer, J. K.; Malashkevich, V. N.; Harrison, J. S.; Toro, R.; Bhosle, R. C.; Chandran, K.; Almo, S. C.; Lai, J. R.*  Crystal Structure of the Marburg Virus GP2 Core Domain in its Post-Fusion Conformation. Biochemistry, 2012, 51, 7665–7675.

Harrison, J. S.; Koellhoffer, J. K.; Chandran, K.; Lai, J. R.*  Marburg Virus Glycoprotein GP2: pH-Dependent Stability of the Ectodomain a-Helical Bundle. Biochemistry, 2012, 51, 2515–2525.

Stewart, A.; Liu, Y.; Lai, J. R.*  A Strategy for Phage Display Selection of Functional Domain-Exchanged Immunoglobulin Scaffolds with High Affinity for Glycan Targets. J. Immunol. Methods, 2012, 376, 150–155.

Liu, Y.; Regula, L. K.; Stewart, A.; Lai, J. R.*  Synthetic Fab Fragments that Bind the HIV-1 Heptad Repeat Regions.  Biochem. Biophys. Res. Commun., 2011, 413, 611–615.

Harrison, J. S.; Higgins, C. D.; Chandran, K.; Lai, J. R.*  Designed Protein Mimics of the Ebola Virus Glycoprotein GP2 α-Helical Bundle: Stability and pH Effects. Protein Sci., 2011, 20, 1587–1596.

Miller, E. H.; Harrison, J. S.; Radoshitzky, S. R.; Higgins, C. D.; Chi, X.; Dong, L.; Kuhn, J. H.; Bavari, S.; Lai, J. R.*; Chandran, K.*  Inhibition of Ebola Virus Entry by a C-Peptide Targeted to Endosomes.  J. Biol. Chem., 2011, 286, 15854–15861.

Da Silva, G. F.; Harrison, J. S.; Lai, J. R.*  Contribution of Light Chain Residues to High Affinity Binding in an HIV-1 Antibody Explored by Combinatorial Scanning Mutagenesis.  Biochemistry, 2010, 49, 5464–5472.



More Information About Dr. Jonathan Lai

Lai Group Webpage

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Media Coverage

NY1 interviews Dr. Jonathan Lai about his research on Ebola that focuses on developing antibodies to use as a possible treatment for all five strains of the virus.

More media coverage