Intracellular Processing and Delivery Agents

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Researchers: Souvik Ghosal, Azmain Alamgir and Allison Chen

Intracellular Processing of Antibody-drug Conjugates

Cleavable, heteromultifunctional chemical cross-linkers have proven critical in a wide range of biological applications such as protein enrichment, conjugate-based drug delivery, and nanoparticle surface functionalization. However, traditional approaches for synthesizing this class of compounds suffer from various synthetic and functional limitations. Leveraging the oligoTEA synthesis methodology developed in our lab, we have recently addressed many of these limitations. In this research thrust, we utilize oligoTEA synthesis to design novel degradable scaffolds for the delivery of small molecule chemotherapeutics and molecular probes for the quantification of fundamental biological processes. 

Engineering OligoTEAs for Effective Cellular Entry

Precise control over primary sequence and composition of oligoTEAs allows us to create synthetic alternatives to functional peptides. Compared to native peptides, oligoTEAs are proteolytically stable and yet easy to assemble at scale with structural diversity. In addition, access to direct modification of the oligoTEA backbone enables conformational control for tuning interactions between the binding motifs and the cell membrane. We have discovered a new class of non-charged cell-penetrating oligoTEAs (CPOTs) that undergo rapid cellular entry  across a variety of cell lines (see video below). Experiments suggest that they undergo direct translocation across the cell membrane. We are currently focused on using CPOTs to deliver antibiotics against intracellular pathogens.  

Recent Publications

Michelle Sorkin, Joshua A. Walker, Francis Ledesma, Nicole P. Torosian, and Christopher A. Alabi*. Design of Protein-based "turn-on" Molecular Probes for Intracellular Bond Cleavage. Mol. Syst. Des. Eng., 2019, DOI: 10.1039/C9ME00147F

Joshua A. Walker, Michelle Sorkin, Francis Ledesma, Sneha R. Kabaria, Robyn M. Barfield, David Rabuka, and Christopher A. Alabi*. Hydrophilic Sequence-Defined Crosslinkers for Antibody-Drug Conjugates. Bioconjugate Chemistry, 2019, DOI: 10.1021/acs.bioconjchem.9b00713

Michelle Sorkin, Joshua A. Walker, Sneha R. Kabaria, Nicole P. Torosian, and Christopher A. Alabi*. Responsive Antibody Conjugates Enable Quantitation of Intracellular Bond Degradation Rate. Cell Chemical Biology, 2019, DOI: 10.1016/j.chembiol.2019.09.008

Joshua A. Walker, John J. Bohn, Francis Ledesma, Sneha R. Kabaria, Michelle Sorkin, Dana N. Thornlow, and Christopher A. Alabi*. Substrate Design Enables Heterobifunc-tional, Dual “Click” Antibody Modification via Microbial Transglutaminase. Bioconjugate Chemistry, 2019, DOI: 10.1021/acs.bioconjchem.9b00522

Phan NN, Li C and Alabi CA. Intracellular Delivery via Noncharged Sequence-Defined Cell-Penetrating Oligomers. Bioconjugate Chem 2018. DOI: 10.1021/acs.bioconjchem.8b00336

OligoTEA entry into Hela cells

OligoTEA entry into Hela cells

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