Peptide and protein chemistry

Our group is broadly interested in the application of peptide, protein and antibody engineering methods for the discovery and development of novel immunotherapies and vaccines. Projects are highly interdisciplinary and involve aspects such as phage display, structure-based protein design, bispecific antibody engineering, structural biology, virology, and cancer biology. Current direction include:

1.     Engineered antibodies as virus immunotherapies. The use of monoclonal antibodies (mAbs) as therapeutics (immunotherapy) has been highly successful for oncology and other indications, but application of mAbs to viral immunotherapy is only now emerging. mAbs offer an advantage of being highly specific, with little adverse effects. Furthermore, mAbs can engage in Fc-related functions that may serve to promote clearance of infections. We have been using state-of-the-art protein engineering methods to identify, characterize, and evaluate novel virus immunotherapies against Ebola virus, Dengue virus, and Chikungunya virus. We focus on developing new therapeutics by protein engineering that may have features that are not possible with conventional (natural) antibodies.

2.     Immunogen design for flavivirus vaccine discovery. Dengue virus is a mosquito-transmitted flavivirus that causes hundreds of millions of human infections world-wide each year. There are four serotypes of Dengue (DENV1-4) that co-circulate in hyperendemic regions.  Dengue virus vaccine design has been complicated by the recent emergence of Zika virus (ZIKV), another flavivirus. We have been using structure-guided protein engineering to develop novel immunogens that elicit DENV and ZIKV protective antibody responses.  Our strategy focuses on common susceptible epitopes that may be structurally engineered.

3.     Dissection and engineering of protein-protein and protein-antibody interactions by phage display.  Phage display is a combinatorial technique that permits the selection of binding clones from highly diverse protein libraries.  We have used phage display to dissect critical determinants underlying specific protein-protein and protein-antibody interactions. Ultimately, this information can be utilized to design new proteins or antibodies with enhanced function; and contributes generally to our knowledge of protein recognition.  Projects focus on applications in T-cell immunology, chronic lymphocytic leukemia, and viral vaccine design.

 Georgiev, G. I.; Malonis, R. J.; Wirchnianski, A. S.; Wessel, A. W.; Jung, H. S.; Cahill, S. M.; Nyakatura, E. K.; Vergnolle, O.; Dowd, K. A.; Cowburn, D.; Pierson, T. C.; Diamond, M. S.; Lai, J. R.* Resurfaced ZIKV EDIII nanoparticle immunogens elicit neutralizing and protective responses in vivo. Cell Chem. Biol. In press. https://doi.org/10.1016/j.chembiol.2022.02.004.

Malonis, R. J., Earnest, J. T., Kim, A. S., Angeliadis, M., Holtsberg, F. W., Aman, M. J., Jangra, R. K., Chandran, K., Daily, J. P., Diamond, M. S., Kielian, M., Lai, J. R.* Near-germline human monoclonal antibodies neutralize and protect against multiple arthritogenic alphaviruses. Proc. Natl. Acad. Sci. USA, 2021, 118, e2100104118.

Quiroz, J. A., Malonis, R. J., Thackray, L. B., Cohen, C. A., Pallesen, J., Jangra, R. K., Brown, R. S., Hofmann, D., Holtsberg, F. W., Shulenin, S., Nyakatura, E. K., Durnell, L. A., Rayannavar, V., Daily, J. P., Ward, A. B., Aman, M. J., Dye, J. M., Chandran, K., Diamond, M. S., Kielian, M., Lai, J. R.* Human Monoclonal Antibodies against Chikungunya virus Target Multiple Distinct Epitopes in the E1 and E2 Glycoproteins. PLoS Pathog., 2019, 15, e1008061. 

Nyakatura, E. K.; Zak, S. E.; Wec, A. Z.; Hofmann D.; Shulenin, S.; Bakken, R. R.; Aman, M. J.; Chandran, K.; Dye, J. M.; Lai, J. R.* “Design and Evaluation of Bi-and Trispecific Antibodies Targeting Multiple Filovirus Glycoproteins” J Biol Chem., 2018, 293, 6201-6211. (PMCID: PMC5912469).