(194u) Extensive Intracellular Delivery Via Non-Charged Sequence-Defined Cell-Penetrating Oligomers

The discovery of cell-penetrating peptides (CPPs) over two decades ago uncovered a novel method for transporting a variety of cargoes into cells. Although promising, CPPs have several drawbacks that hinder their use for in vivo therapeutic applications such as rapid metabolic degradation by proteases, immunological response, undesired interactions with extracellular matrix components, and nephrotoxicity. Recently, the Alabi group developed an approach for the rapid assembly of sequence-defined oligothioetheramides (oligoTEAs). OligoTEAs have three distinct advantages over native peptides, including i) abiotic design to reduce proteolytic degradation and immune response, ii) backbone and pendant group access to tune interactions, and iii) diverse monomers for massive compositional library.

To overcome these limitations, we have designed and synthesized a new class of non-charged cell-penetrating oligoTEAs (CPOTs) that undergo extensive and rapid cellular entry across different cell lines with low cytotoxicity. CPOTs outperform a widely used CPP, R9 peptide. This new class of highly efficient non-charged macromolecular transporters are distinct from their cationic counterparts and show strong promise for the intracellular delivery of therapeutics. This talk will focus on the sequence controlled assembly of this new class of cell-penetrating agents, their uptake efficiency across a variety of cell lines, and their ability to deliver antibiotics for the treatment of intracellular pathogens.