Dr Dehua Pei is the Charles H. Kimberly Professor of Chemistry and Biochemistry at Ohio State University. His research group is currently developing new methodologies for combinatorial synthesis and screening of macrocyclic peptides/peptidomimetcis, cyclic cell-penetrating peptides for drug delivery, and macrocyclic inhibitors against previously undruggable targets, such as intracellular protein-protein interactions.
In this exclusive interview, he discusses cell penetrating peptides, delivery strategies, and working with commercial developers of peptide and oligonucleotide therapeutics.
You are involved in research regarding delivery strategies for a variety of different molecules. What are the opportunities for people working on different modalities/molecules to learn from each other regarding these delivery challenges?
DP: 'All current non-viral delivery methods face the problem of low cytosolic delivery efficiency, which is believed to be primarily caused by inefficient release from the endosome. Since this is a common problem, improvements with one modality may be applicable to others.'
Why are so many developers of biological modalities experiencing endosomal entrapment during drug delivery?
DP: 'Biological modalities are generally internalized by cells through various forms of endocytosis and initially ended up inside the early endosomes. The early endosomes then mature into late endosomes and finally fuse with the lysosome. Unless something is done to facilitate the drug molecules’ escape from these vesicles, they will be sent into the lysosome and degraded, just like the nutrient molecules. Some viruses and bacterial toxins have evolved mechanisms to efficiently escape the endosomal/lysosomal pathway, but the molecular details of these mechanisms are unknown. Without a mechanistic understanding of the escape process, most drug developers rely on empirical approaches, which have had limited success.'
Why are cell penetrating peptides advantageous as a delivery vehicle for macromolecular therapeutics?
DP: 'I am not sure that cell-penetrating peptides are necessarily better delivery vehicles than others, but after three decades of intense efforts, we are finally gaining a good understanding of how the CPPs work including their mechanism of endosomal escape. Armed with this knowledge, we can now design/test CPPs for improved endocytic uptake and endosomal escape efficiencies. The same knowledge may be used to improve the performance of other delivery vehicles.'
How can academic research from your lab benefit commercial developers of peptide and oligonucleotide therapeutics?
DP: 'We discovered a family of small cyclic peptides as exceptionally active and bioavailable CPPs. We have also elucidated their mechanism of action (i.e., endocytic uptake followed by highly efficient release from the early endosome). We have demonstrated that these cyclic CPPs can efficiently deliver small molecules, linear peptides, cyclic peptides, proteins, and nucleic acids into the cytosol of mammalian cells in vitro and in vivo.
We have developed macrocyclic peptidyl inhibitors against a variety of previously undruggable targets including those involved in intracellular protein-protein interactions (e.g., Ras-effector interaction). Some of these agents have demonstrated favorable pharmacokinetics and in vivo efficacy in animal models.'
