Peptide-Like Molecules (PLMs): A Journey from Peptide Bond Isosteres to Gramicidin S Mimetics and Mitochondrial Targeting Agents

Abstract

Peptides are natural ligands and substrates for receptors and enzymes and exhibit broad physiological effects. However, their use as therapeutic agents often suffers from poor bioavailability and insufficient membrane permeability. The success of peptide mimicry hinges on the ability of bioisosteres, in particular peptide bond replacements, to adopt suitable secondary structures relevant to peptide strands and position functional groups in equivalent space. This perspective highlights past and ongoing studies in our group that involve new methods development as well as specific synthetic library preparations and applications in chemical biology, with the goal to enhance the use of alkene and cyclopropane peptide bond isosteres.

On the Terminal Homologation of Physiologically Active Peptides as a Means of Increasing Stability in Human Serum – Neurotensin, Opiorphin, B27‐KK10 Epitope, NPY

“…Extended regions of both of the mentioned connectivities point to conformational averaging between the a r and the b region of f,y-space [97]. For 2a, however, we also observed a weak but clearly visible cross-peak between H(a) 10 and HN 12 . Such a cross-peak together with the one between HN 11 and HN 12 is indicative for a b-turn [97].…”

“…8. A second set of signals in the spectra of both compounds is attributed to the cisisomer of Pro 10 . The cis/trans ratio is 1 : 5 for 2a and 1 : 4 for 2c (the trans-isomer is identified based on the strong ROESY cross-peak between Arg 9 H(a) and Pro 10 H(d)).…”

“…The structural differences and the resulting differences of folded conformations (turns, helices) of a-and b-peptides prevent mimicking a-peptidic structures and physiological properties by peptides consisting entirely of b-amino acid residues, except in special cases 10 ). The question arose, whether partial replacement of a-amino acid residues by backbone-expanded w-amino acid residues in proteins and in peptides is possible without loss of structure and/or functions.…”

Synthesis of analogs of the radiation mitigator JP4-039 and visualization of BODIPY derivatives in mitochondria

“…GS adopts a type II′ β-turn structure that buries several polar amide groups inside the molecule and thus may facilitate membrane transport. 4,5 Both XJB-5–131 and JP4-039 fold into a β-turn secondary structure in the solution and solid state, respectively, and exhibited enrichments of 30- to 600-fold in mitochondria. 1,6 Localization of ROS trapping agents to mitochondria is important since ca.…”

Allylic Amines as Key Building Blocks in the Synthesis of (E)-Alkene Peptide Isosteres

“…In order for a rational design of these compounds to be effective, they must be able to adopt secondary structures typical for native peptides. 3 Among others, methylene amine, 4 ketomethylene, 5 hydroxyethylamine, 6 hydroxymethylene and hydroxyethylene, 7 dihydroxyethylene, 8 cyclopropylalkylamine, 9 methyl- and (trifluoromethyl)alkenes, 10 and β-amino acids 11 have been used for this purpose. Our group has studied ( E )-alkenes 9b,10b,12 as peptide bond replacements (Figure 3), 3b,13 and the synthesis and applications of these isosteres as mitochondrial targeting compounds 14 is a major focus of our program.…”