Lai group

Welcome to the Lai lab website


The Lai group is part of the Biochemistry Department at Albert Einstein College of Medicine

About us


About us

Welcome to the Lai Group official website!
Our lab is located in Michael F. Price Center, Albert Einstein College of Medicine

Contact Info:
Michael F. Price Center
1301 Morris Park Avenue, Room 519
Bronx, NY 10461
Tel: 718-678-1024
jon.lai@einstein.yu.edu





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 directions 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.

Research


Immunogen engineering

Dengue virus is an enveloped virus of which there are four co-circulating serotypes (DENV1-4), which annually give rise...

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Multispecific Antibody Engineering

Monoclonal antibodies (mAbs) against the envelope glycoprotein represent a promising therapeutic platform

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Human monoclonal antibody isolation

A large number of protective mAbs to CHIKV glycoprotein have been isolated from...

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Personalized cancer immunotherapy

The success of  Chimeric Antigen Receptor T-cell therapy (CAR TCTx) in leukemia has been difficult to translate...

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Publications


List of publications:

  1. Dai, Z.; Lai, J. R. Isolation of Synthetic Antibodies Against BCL2-Associated X Protein (BAX). Methods Mol. Biol., 2019, 1877, 351-357. [[Journal link]]
  2. Saphire, E. O.; Schendel, S. L.; Fusco, M. L.; Gangavarapu, K.: Gunn, B. M.; Wec, A. Z.; Halfmann, P. J.; Brannan, J. M.; Herbert, A. S.; Qiu, X.; Wagh, K.; He, S.; Giorgi, E. E.; Theiler, J.; Pommert, K. B. J.; Krause, T. B.; Turner, H. L.; Murin, C. D.; Pallesen, J.; Davidson, E.; Ahmed, R.; Aman, M. J.; Bukreyev, A.; Burton, D. R.; Crowe, J. E. Jr; Davis, C. W.; Georgiou, G.; Krammer,F.; Kyratsous. C. A.; Lai, J. R.; Nykiforuk, C.; Pauly, M. H.; Rijal, P.; Takada, A.; Townsend, A.R.; Volchkov, V.; Walker, L. M.; Wang, C. I.; Zeitlin, L.; Doranz, B. J.; Ward, A. B.; Korber, B.; Kobinger, G. P.; Andersen, K. G.; Kawaoka, Y.; Alter, G.; Chandran, K.; Dye, J. M.; Viral Hemorrhagic Fever Immunotherapeutic Consortium. Systematic Analysis of Monoclonal Antibodies against Ebola Virus GP Defines Features that Contribute to Protection. Cell, 2018, 174, 938-952. [[Journal link]]
  3. Gunn, B. M.; Yu, W. H.; Karim, M. M.; Brannan, J. M.; Herbert, A. S.; Wec, A.Z.; Halfmann, P. J.; Fusco, M. L.; Schendel, S. L.; Gangavarapu, K.; Krause, T.; Qiu, X.; He, S.; Das, J.; Suscovich, T.J.; Lai, J.R.; Chandran, K.; Zeitlin, L.; Crowe, J. E. Jr; Lauffenburger, D.; Kawaoka, Y.; Kobinger, G.P.; Andersen, K. G.; Dye, J. M.; Saphire, E. O.; Alter, G. A Role for Fc Function in Therapeutic Monoclonal Antibody-Mediated Protection against Ebola Virus. Cell Host Microbe, 2018, 24, 221-233. [[Journal link]]
  4. Jangra RK, Herbert AS, Li R, Jae LT, Kleinfelter LM, Slough MM, Barker SL, Guardado-Calvo P, Román-Sosa G, Dieterle ME, Kuehne AI, Muena NA, Wirchnianski AS, Nyakatura EK, Fels JM, Ng M, Mittler E, Pan J, Bharrhan S1, Wec AZ, Lai JR, Sidhu SS, Tischler ND, Rey FA, Moffat J, Brummelkamp TR, Wang Z, Dye JM, Chandran K. Protocadherin-1 is essential for cell entry by New World hantaviruses. Nature 2018, 563(7732), 559-563. [[Journal link]]
  5. Frei, J. C.; Wirchnianski, A. S.; Govero, J.; Vergnolle,O; Dowd, K. A.; Pierson, T. C.; Kielian, M; Girvin M. E.; Diamond, M. S.; Lai, J. R. Engineered Dengue Virus Domain III Proteins Elicit Cross-Neutralizing Antibody Response in Mice. J.Virol. 2018, 92(18) [[Journal link]]
  6. 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. [[Journal link]]
  7. Lin, T.Y.; Lai, J. R. Interrogation of Side Chain Biases for Oligomannose Recognition in Antibody 2G12 via Structure-Guided Phage Display Libraries. Bioorg. Med. Chem, 2017, 25, 5790-5798. [[Journal link]]
  8. Hofmann, D. H.; Zak, S. E.; Nyakatura, E. K.; Mittler, E.; Bakken, R. R.; Chandran, K.; Dye, J. M.; Lai, J. R. Mechanistic and Fc Requirements for Inhibition of Sudan Virus Entry and In Vivo Protection by a Synthetic Antibody.  Immunol. Lett., 2017, 190, 289-295 [[Journal link]]
  9. Wec, A. Z.; Herbert, A. S.; Murin, C. D.; Nyakatura, E. K.; Abelson, D. M.; Fels, J. M.; He, S.; James, R. M.; de La Vega, M. A.; Zhu, W.; Bakken, R. R.; Goodwin, E.; Turner, H. L.; Jangra, R. K.; Zeitlin, L.; Qiu, X.; Lai, J. R.; Walker, L. M.; Ward, A. B.; Dye, J. M.*; Chandran, K.*; Bornholdt, Z. A.* Antibodies from a Human Survivor Define Sites of Vulnerability for Broad Protection against Ebolaviruses. Cell, 2017, 169, 878-890. [[Journal link]] 
  10. Hofmann, D.; Lai, J. R. Exploring Human Antimicrobial Antibody Responses on a Single B Cell Level. Clin. Vaccine Immunol., 2017, 24, pii: e00544-16. [[Journal link]]
  11. Nyakatura, E. K.; Soare, A. Y.; Lai, J. R. Bispecific Antibodies for Viral Immunotherapy. Hum. Vaccin. Immunother., 2017, 13, 836-842 [[Journal link]]
  12. Wec, A. Z.+; Nyakatura, E. K.+; Herbert, A. S.+; Howell, K. A.; Holtsberg, F. W.; Bakken, R. R.; Mittler, E.; Christin, J. R.; Shulenin, S.; Jangra, R. K.; Bharrhan, S.; Kuehne, A. I.; Bornholdt, Z. A.; Flyak, A. I.; Saphire, E. O.; Crowe, J. E.*; Aman, M. J.*; Dye, J. M*; Lai, J. R.*; Chandran, K.* A "Trojan Horse" Bispecific Antibody Strategy for Broad Proteciton against Ebolaviruses. Science, 2016, 354, 350-354.(+Equal contributors) [[Journal link]]
  13. Frei, J. C.; Lai, J. R.* Protein and Antibody Engineering by Phage Display. Methods Enxymol., 2016, 580, 45-87. [[Journal link]]
  14. Howell, K. A.; Qiu, X.; Brannan, J. M.; Bryan, C.; Davidson, E.; Holtsberg, F. W.; Wec, A. Z.; Shulenin, S.; Biggins, J. E.; Douglas, R.; Enterlein, S. G.; Turner, H. L.; Pallesen, J.; Murin, C. D.; He, S.; Vu, H.; Herbert, A. S.; Fusco, M. L.; Nyakatura, E. K.; Lai, J. R.; Keck, Z. Y.; Foung, S. K.; Saphire, E. O.; Zeitlin, L.; Ward, A. B.; Chandran, K.; Doranz, B. J.; Kobinger, G. P.; Dye, J. M.; Aman, M. J.* Antibody Treatment of Ebola and Sudan Virus Infection via a Uniquely Exposed Epitope within the Glycoprotein Receptor-Binding Site. Cell Rep., 2016, 15, 1514-1526. [[Journal link]]
  15. Frei, J. C.+; Nyakatura, E. K.+; Zak, S. E.+; Bakken, R. R.; Chandran, K.; Dye, J. M.*; Lai, J. R.*  Bispecific Antibody Affords Complete Post-Exposure Protection of Mice from Both Ebola (Zaire) and Sudan Viruses.  Sci. Rep., 2016, 6, 19193.  [[Journal link]] 
  16. Uchime, O.+; Dai, Z.+; Biris, N.; Lee, D., Sidhu, S. S., Li, S., Lai, J. R.*, Gavathiotis, E.*  Synthetic Antibodies Inhibit Bcl-2-associated X Protein (BAX) through Blockade of the N-terminal Activation Site.  J. Biol. Chem., 2016, 291, 89-102.  [[Journal link]]
  17. Holtsberg FW, Shulenin S, Vu H, Howell KA, Patel SJ, Gunn B, Karim M, Lai JR,  Frei JC, Nyakatura EK, Zeitlin L, Douglas R, Fusco ML, Froude JW,  Saphire EO, Herbert AS, Wirchnianski AS, Lear-Rooney CM, Alter G, Dye  JM, Glass PJ, Warfield KL, Aman MJ. Pan-ebolavirus and Pan-filovirus Mouse Monoclonal Antibodies: Protection against Ebola and Sudan Viruses.  J. Virol., 2015, 90, 266-289.  [[Journal link]]
  18. Frei, J. C.; Kielian, M., Lai, J. R.* Comprehensive Mapping of Functional Epitopes on Dengue Virus Glycoprotein E DIII for Binding to Broadly Neutralizing Antibodies 4E11 and 4E5A by Phage Display.  Virology, 2015,485, 371-382.  [[Journal link]]
  19. Malashkevich, V. N.; Higgins, C. D.+; Almo, S. C.*; Lai, J. R.*  A Switch from Parallel to Antiparallel Strand Orientation in a Coiled-Coil X-Ray Structure via Two Hydrophobic Mutations.  Biopolymers: Peptide Science, 2015, 104, 178-185. [[Journal link]]
  20. Liu, N.; Tao, Y.; Brenowitz, M. D.; Girvin, M. E.; Lai, J. R.* Structural and Functional Studies on the Marburg Virus GP2 Fusion Loop.  In press at J. Infect. Dis. [[Journal link]]
  21. Dai, Z.; Tao, Y.; Brenowitz, M. D.; Girvin, M.E.; Lai, J. R.*  Conditional Trimerization and Lytic Activity of HIV-1 gp41 Variants Containing the Membrane-Associated Segments.  Biochemistry, 2015, 54, 1589-1599.  [[Journal link]]
  22. Nyakatura, E. K.; Frei, J. C.; Lai, J. R.* Chemical and Structural Aspects of Ebola Virus Entry Inhbitors.  ACS Infect. Dis., 2015, 1, 42-52. [[Journal link]]
  23. Chen, G.+; Koellhoffer, J. F.+; Zak, S. E.+; Frei, J. C.; Liu, N.; Long, H.; Yi, 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.  ACS Chem. Biol., 2014, 9, 2263-2273. [[Journal link]] Press coverage of this work: NY1, NY Daily News, FrontPageAfrica, Chemical & Engineering News, Quartz, Infection Control Today, Einstein1, Einstein2
  24. Higgins, C. D.; Malashkevich, V. N.; Almo, S. C.; Lai. J. R.* Influcence of a Heptad Repeat Stutter on the pH-Dependent Conformational Behavior of the Central Coiled-Coil from Influenza Hemagglutinin HA2.  Proteins, 2014, 82, 2220-2229. [[Journal link]]
  25. 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.   [[Journal link]]
  26. 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.  [[Journal link]]
  27. Liu, Y.; Higgins, C. D.; Overstreet, C. M.; Rai, K. R.; Chiorazzi, N.*; Lai, J. R.*  Peptides that Bind Specifically to an Antibody from a Chronic Lymphocytic Leukemia Clone Expressing Unmutated Immunoglobulin Variable Region Genes.  Mol. Medicine, 2013, 19, 245-252.  [[Journal link]]
  28. 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.  [[Journal link]]
  29. 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.  [[Journal link]]
  30. Regula, L. K.; Harris, R.; Wang, F.; Higgins, C. D.; Koellhoffer, J. K.; Zhao, Y.; Chandran, K.; Gao, J.; Girvin, M. E.; Lai, J. R.* Conformational Properties 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.  [[Journal link]]
  31. 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, 4, 9.  [[Journal link]]
  32. Koellhoffer, J. L.+; 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.  [[Journal link]]
  33. 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, 7665-7775.  [[Journal link]]
  34. Harrison, J. S.; Koellhoffer, J. K.; Chandran, K.; Lai, J. R.*  Marburg Virus Glycoprotein GP2: pH-Dependent Stability of the Ectodomain alpha-Helical Bundle.  Biochemistry, 2012, 51, 2515-2525. [[Journal link]]
  35. 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. [[Journal link]] 
  36. 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. [[Journal link]] 
  37. Harrison, J. S.+; Higgins, C. D.+; Chandran, K.; Lai, J. R.*  Designed Protein Mimics of the Ebola Virus Glycoprotein GP2 alpha-Helical Bundle: Stability and pH Effects.  Protein Sci., 2011, 20, 1587-1596. [[Journal link]]
  38. 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. C.*  Inhibition of Ebola Virus Entry by a C-Peptide Targeted to Endosomes.  J. Biol. Chem. 2011, 286, 15854-15861.  [[Journal link]]
  39. 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.  [[Journal link]]


Publications during Ph.D. and Postdoctoral Fellowship:

  • Pomerantz, W. C.; Grygiel, T. L. R.; Lai, J. R.; Gellman, S. H.  Distinctive Circular Dichroism Signature for 14-Helix-Bundle Formation by beta-Peptides.  Org. Lett. 2008, 10, 1799–1802.  [[Journal link]]
  • Fischbach, M. A.; Lai, J. R.; Roche, E. D.; Walsh, C. T.; Liu, D. R.  Directed Evolution Can Rapidly Improve the Activity of Chimeric Assembly-Line Enzymes.  Proc. Natl. Acad. Sci. USA 2007, 104, 11951–11956.  [[Journal link]]
  • Zhou, Z.; Lai, J. R.; Walsh, C. T.  Directed Evolution of Aryl Carrier Proteins: Determinants of Recognition in the Enterobactin Synthetase.  Proc. Natl. Acad. Sci. USA 2007, 104, 11621–11626.  [[Journal link]]
  • Lai, J. R.; Koglin, A.; Walsh, C. T.  Carrier Protein Structure and Recognition in Polyketide and Nonribosomal Peptide Biosynthesis.  Biochemistry 2006, 45, 14869–14879.  [[Journal link]]
  • Lai, J. R.; Fischbach, M. A.; Liu, D. R.; Walsh, C. T.  Localized Protein Interaction Surfaces on the EntB Carrier Protein Revealed by Combinatorial Mutagenesis and Selection.  J. Am. Chem. Soc. 2006, 128, 11002–11003.  [[Journal link]]
  • Zhou, Z.; Lai, J. R.; Walsh, C. T.  Interdomain Communication Involving the Thiolation Domain of EntF Explored by Combinatorial Mutagenesis and Selection.  Chem. Biol. 2006, 13, 869–879.  [[Journal link]]
  • Lai, J. R.; Fischbach, M. A.; Liu, D. R.; Walsh, C. T.  A Protein Interaction Surface in Nonribosomal Peptide Synthesis Mapped by Combinatorial Mutagenesis and Selection.  Proc. Natl. Acad. Sci. USA 2006, 103, 5314–5319.  [[Journal link]]
  • Lai, J. R.+; Epand, R. F.+; Weisblum, B.; Epand, R. M.; Gellman, S. H.  Role of Salt and Conformation in the Biological and Physicochemical Behavior of Protegrin-1 and Designed Analogues: Correlation of Antimicrobial, Hemolytic and Lipid Bilayer-Perturbing Activities.  Biochemistry 2006, 45, 15718–15730.  [[Journal link]]
  • Lai, J. R.; Fisk, J. D.; Weisblum, B.; Gellman, S. H.  Hydrophobic Core Repacking in a Coiled-Coil Dimer via Phage Display: Insights into Plasticity and Specificity at a Protein-Protein Interface.  J. Am. Chem. Soc. 2004, 126, 10514–10515.  [[Journal link]]
  • Park, J. S.; Lee, H. S.; Lai, J. R.; Kim, B. M.; Gellman, S. H.  Accommodation of alpha-Substituted Residues in the alpha-Peptide 12-Helix: Expanding the Range of Substitution Patterns Available to a Foldamer Scaffold.  J. Am. Chem. Soc. 2003, 125, 8539–8545.  [[Journal link]]
  • Raguse, T. L.; Lai, J. R.; Gellman, S. H.  Environment-Independent 14-Helix Formation in Short beta-Peptides: Striking a Balance between Shape Control and Functional Diversity.  J. Am. Chem. Soc. 2003, 125, 5592–5593.  [[Journal link]]
  • Lai, J. R.; Gellman, S. H.  Reinvestigation of the Proposed Folding and Self-Association of the Neuropeptide Head Activator.  Protein Sci. 2003, 12, 560–566.  [[Journal link]]
  • Raguse, T. L.; Lai, J. R.; Gellman, S. H.  Evidence that the beta-Peptide 14-Helix is Stabilized by beta-3-Residues with Side-Chain Branching Adjacent to the beta-Carbon.  Helv. Chim. Acta 2002, 85, 4154–4164.  [[Journal link]]
  • Lai, J. R.; Huck, B. R.; Weisblum, B.; Gellman, S. H.  Design of Non-Cysteine-Containing Antimicrobial beta-Hairpins: Structure-Activity Relationship Studies with Linear Protegrin-1 Analogues.  Biochemistry 2002, 41, 12835–12842.  [[Journal link]]
  • Raguse, T. L.; Lai, J. R.; LePlae, P. R.; Gellman, S. H.  Toward beta-Peptide Tertiary Structure: Self-Association of an Amphiphilic 14-Helix in Aqueous Solution.  Org. Lett. 2001, 3, 3963–3966.  [[Journal link]]
  • Woll, M. G.; Lai, J. R.; Guzei, I. A.; Taylor, S. J. C.; Smith, M. E. B.; Gellman, S. H.  Parallel Sheet Secondary Structure in gamma-Peptides.  J. Am. Chem. Soc. 2001, 123, 11077–11078.  [[Journal link]]

Lab Members


Jon Lai

Principal Investigator

Olivia Vergnolle

Lab Manager

Elisabeth K. Nyakatura

Research Assistant Professor

Leslie Ann Diaz

Technician

Srinjoy Chakraborti

Postdoctoral Fellow

Jose Quiroz

MD/PhD student

Alexander Ramek

MD/PhD student

Ryan Malonis

MD/PhD student

George Georgiev

PhD student

Leandrew Dailey

PREP Student

Alumni from the Lai Lab

Alumni

Contact Us


  • Albert Einstein College of Medicine of Yeshiva University - Jack and Pearl Resnick Campus, Bronx, NY, USA