Strategies to Discover, Design, and Synthesize Unnatural Bioactive Peptides

• Dr. Carly Schissel, University of California, Berkeley
• Sponsored by Stanford Chemistry Department
• 3:00-4:00 pm, Sapp Center Auditorium 111, 376 Lomita Dr., Stanford Univ., Learn more

“Peptide therapeutics are a rapidly expanding frontier in drug development. New methods that address challenges in the discovery, design, and synthesis of bioactive peptides are needed to advance these molecules as medicines. One of the most important roadblocks that macromolecular drugs face is their inability to reach intracellular targets. I will demonstrate new approaches for the design and synthesis of unnatural bioactive peptides. First, we used machine learning for the de novo design of nuclear-targeting miniproteins to traffic macromolecular cargo to the nucleus of cells. We found that the model was able to predict new sequences with activities extrapolated beyond the training dataset, resulting in the most active variants yet. Next, we demonstrated a method for in-cell penetration selection–mass spectrometry to discover cytosol-targeting peptides from a synthetic library. Novel unnatural sequences found from the cytosol trafficked oligonucleotide cargo to the nucleus better than those found in whole cell extracts. A key outcome of these efforts was that the presence of unnatural amino acids with extended backbones conferred enhanced bioactivity. The ribosomal synthesis of proteins and peptides with unnatural peptide backbones is thus of critical importance. In the second part of the presentation, we developed post-translational acyl shift reactions to install internal diketones, heterocycles, and extended backbones in ribosomal peptides and proteins. These works advance the therapeutic potential of peptides by both developing new bioactive sequences and enabling their biological synthesis.

About the Speaker

Carly grew up in San Diego, California, and earned her BA in Chemistry from Williams College, where she worked under the mentorship of Prof. Thomas Smith to complete the total synthesis of the polyketide Jerangolid D. She pursued her Ph.D. in Chemistry at the Massachusetts Institute of Technology, working with Prof. Brad Pentelute. Her doctoral research focused on designing peptide sequences for the nuclear delivery of macromolecules, employing machine learning-guided design and in-cell selection strategies. In March 2022, Carly joined the University of California, Berkeley, as a Miller Institute Postdoctoral Fellow, hosted by Prof. Alanna Schepartz. Her current research centers on developing peptide backbone editing reactions, including the substitution of canonical amide bonds with carbon-carbon bonds.”

Host: Steven Banik