Intracellular Processing and Delivery Agents
Researchers: Michelle R. Sorkin, Joshua A. Walker, Dana N. Thornlow, and Ngoc N. Phan
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.
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
Sorkin MR, Walker JA, Brown JS, and Alabi CA. Versatile Platform for the Synthesis of Orthogonally Cleavable Heteromultifunctional Cross-Linkers. Bioconjugate Chem 2017. DOI: 10.1021/acs.bioconjchem.7b00033