Natural product discovery has been at the root of modern drug design, and it continues to play a vital role as there is renewed focus on orally available peptide therapeutics. In particular, macrocyclic peptides often exhibit desirable characteristics such as high receptor-binding activity and specificity, metabolic stability, and cell permeability.
Examples of uniquely structured bioactive peptides with exceptional stability are cyclosporine-A, an immunosuppressant whose structure is rich in N-methylation, microcin J25, an antibacterial lasso peptide, and kalata-B1, a cyclotide with insecticidal activity. However, discovery efforts have been hindered in part by sequencing difficulties.
In work published in Angewandte Chemie, Intl.Ed., researchers in the Raj Group report a simple chemical sequencing method that overcomes the challenges of existing analytical techniques for highly stable macrocyclic and lasso peptides.
This site-selective cleavage methodology is applicable to peptides containing Ser, Thr, Cys, or Glu residues, due to their ability to form a cyclic urethane-derived moiety that is susceptible to cleavage, see figure. These residues are present in approximately 60% of naturally occurring macrocyclic peptides and 66% of lasso peptides as determined by a survey of NORINE, a cyclic peptide database, and a comprehensive list of all lasso peptides discovered to date.
This method is also applicable to several less common amino acids found in nonribosomal peptides containing reactive β- or γ-hydroxyl side chains, such as β-hydroxylphenylalanine and homoserine.
Ultimately, this chemical cleavage method will provide a generic approach for synthesizing interlocking peptides that could be used to make peptide-based supramolecular structures such as catenanes, peptide daisy chains, and quasiâ€catenanes from lasso scaffolds. Work in this direction is currently underway in the Raj laboratory.
Cyclic and Lasso Peptides: Sequence Determination, Topology Analysis, and Rotaxane Formation
Hader E. Elashal, Ryan D. Cohen, Heidi E. Elashal, Dr. Chuhan Zong, Prof.â€…Dr. A. James Link, Prof.â€…Dr. Monika Raj
Angew. Chemie, Intl. Ed., Volume57, Issue 21, May 22, 2018, Pages 6150-6154