Membrane-Inserting Peptides
Yana Reshetnyak
Professor, University of Rhode Island
Macrocyclic peptides possess a number of pharmacological characteristics distinct from other well-established therapeutic molecular classes, resulting in a versatile drug modality with a unique profile of advantages. Macrocyclic peptides are accessible by not only chemical synthesis but also ribosomal synthesis. Particularly, recent inventions of the genetic code reprogramming integrated with an in vitro display format, referred to as RaPID (Random non-standard Peptides Integrated Discovery) system, have enabled us to screen mass libraries (>1 trillion members) of non-standard peptides containing multiple non-proteinogenic amino acids, giving unique properties of peptides distinct from conventional peptides, e.g. greater proteolytic stability, higher affinity (low nM to sub nM dissociation constants similar to antibodies), and superior pharmacokinetics. The field is rapidly growing evidenced by increasing interests from industrial sectors, including small start-ups as well as mega-pharmas, toward drug development efforts on macrocyclic peptides, which has led to several de novo discovered peptides entering clinical trials. This lecture discusses the aforementioned screening technology, the RaPID system, and several showcases of therapeutic potentials of macrocyclic peptides. This lecture also discusses the most recent advance in the display of pseudo-natural products generated by thiopeptide post-translationally modifying enzymes.
Yana is a Professor of physics at the University of Rhode Island. She graduated from Saint-Petersburg University, Physics Department in 1993 and received PhD in Biophysics in 2000 followed by 2 postdoctoral trainings at the University of North Texas and Yale University. In 2004, she joined the University of Rhode Island Physics Department as an NSF Faculty Fellow. Her expertise is in membrane biophysics, protein and peptide physics, fluorescence spectroscopy, microscopy, in vivo fluorescence imaging and drug delivery. In my laboratory we study the molecular mechanism of membrane-associated folding/unfolding employing steady-state and kinetics spectral approaches and use this knowledge to develop a new class of pH-sensitive delivery agents. She has demonstrated that pHLIP can target acidic solid tumors with high accuracy, and now pHLIP is considered as a novel pH-sensitive delivery agent and it is translated to clinics. She is co-author in 90 peer-reviewed published papers and co-inventor of pHLIP technology (>60 patents/patent applications).