The proposed project seeks to further characterize a unique class of cell-penetrating peptides (CPPs) capable of translocating through the cell membrane independent of endocytosis and without compromising the physiology of the cell membrane. We hypothesize that CPPs with these distinct features, referred to as membrane translocating peptides (MTPs), can be engineered to facilitate cell-impermeable therapeutics directly (spontaneously) into cells. In order to establish an efficient peptide based delivery platform must take into account the mechanism of cellular entry. Two possible mechanisms of cellular entry exist for CPP- conjugates; energy-dependent processes involving endocytosis or energy-independent processes involving spontaneous direct translocation. Utilizing endocytosis for cellular entry poses problems of endosomal sequestration and degradation of CPP-conjugates. Therefore, our engineering goals for MTPs and MTP- conjugates are to ensure that the cellular uptake mechanism relies upon spontaneous translocation.
The specific aims of this project will identify and optimize MTP sequences for spontaneous translocation followed by assessing the limitations of MTPs to deliver a range of cell-impermeable cargoes into cells. Broader implications from this project will serve to expand what is currently considered feasible to improve the bioavailability of potential therapeutics once associated with MTPs. Drug design strategies could also improve with associations with MTPs by considering potential drug candidates once overlooked for being cell-impermeable.
Drug targets located inside of the cell pose limitations on drug design because of the barrier that the cell membrane presents. This project seeks to design peptides that will help the delivery potentially beneficial drugs into cells that were once thought unable to pass through the barrier of the cell membrane. The proposed project could expand the capabilities of new drug design and development.
| Fuselier, Taylor; Wimley, William C (2017) Spontaneous Membrane Translocating Peptides: The Role of Leucine-Arginine Consensus Motifs. Biophys J 113:835-846 |
| Krauson, Aram J; Hall, O Morgan; Fuselier, Taylor et al. (2015) Conformational Fine-Tuning of Pore-Forming Peptide Potency and Selectivity. J Am Chem Soc 137:16144-52 |
| Kauffman, W Berkeley; Fuselier, Taylor; He, Jing et al. (2015) Mechanism Matters: A Taxonomy of Cell Penetrating Peptides. Trends Biochem Sci 40:749-764 |
