UC Santa Cruz

The passive membrane permeability of cyclic peptides continues to astonish and inspire a growing number of researchers. While the literature has become increasingly dense and the methods of studying cyclic peptides have become more powerful, the problem of turning these molecules into drugs remains. Although cyclic peptides thoroughly violate the previously embraced rules of drug discovery, synthetic investigation leading to de novo discovery in the chemical space beyond traditional small molecule drugs has concentrated on head-to-tail cyclic peptides. Many bioactive peptide natural products with intracellular targets are not head-to-tail cyclized, but rather side chain to tail cyclized resulting in cyclic/linear hybrid peptides known as lariat peptides. We pursued two strategies to study structure-permeability relationships in lariat peptides. Chapter 1 describes the use of synthetic libraries to explore a generic lariat peptide chemical space. We generated a library of scaffolds using stable isotopes to encode stereochemistry and determined the passive membrane permeability of over 1000 novel lariat peptide scaffolds with molecular weights around 1000. Many lariats were surprisingly permeable, comparable to many known orally bioavailable drugs. Passive permeability was strongly dependent on N-methylation, stereochemistry, and ring topology. A variety of structure-permeability trends were observed including a relationship between alternating stereochemistry and high permeability, as well as a set of highly permeable consensus sequences. Chapter 2 describes our investigation of xentrivalpeptides, a class of lariat peptide natural products. These lariats are composed entirely of simple lipophilic amino acids, indicating potential passive permeability. These compounds are heavily enriched in valine, suggesting a possible role of β-branching. We established high permeability for xentrivalpeptide A and prepared several analogues of xentrivalpeptide A to probe the roles of β-branching and stereochemistry. Our results reveal that β-branching is not important for permeability while stereochemistry does influence permeability. Obtaining low-dielectric NMR data proved difficult for these lariats and, having established that lariat peptides can achieve passive permeability, we directed our efforts towards the library approach discussed in chapter 1.