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.

Fig. 1

Recent examples of biologically active peptide bond isosteres.

Fig. 2

Amide bond linkage in peptides (5) and common isosteric replacements 6–11.

Fig. 3

Representative PLM scaffolds.

Fig. 4

Typical alkene based PLMs obtained from alkenylaziridine openings. Diastereoselectivities ranged from 60 to >98% and yields were 50–90%.

Fig. 5

α,β-Cyclopropyl-γ-amino acids building blocks are related to vinylogous amino acids found in natural products.

Fig. 6

First-generation phenylglycine-derived α,β-cyclopropyl-γ-amino acids.

Fig. 7

Sequences of PLMs with phenylglycine-derived α,β-cyclopropyl-γ-amino acids and X-ray structure of a hydrogen-bond connected β-sheet in dimer 69.

Fig. 8

Gramicidin S analogs with selective alkene peptide bond isostere replacements.

Fig. 9

Backbone comparisons based on x-ray structure analyses. Top: Gramicidin S, obtained as the ornithine Boc-protected, partially N-methylated derivative 91; bottom: bis-trifluoroalkene analog 90. Only the backbone carbons and Cβ's of flexible side chains are shown.

Fig. 10

Circular dichroism spectra for GS and analogs 90 (CF3-GS), 96 (CH3-GS), 98 (F-GS), and 106 (H-GS).

Fig. 11

Structure of GS-inspired XJB-5-131.

Scheme 1

Cuprate S_N2′ opening of alkenylaziridines can be used for alkene peptide isostere synthesis.

Scheme 2

Solid phase synthesis of alkene peptide isosteres.

Scheme 3

Imine addition cascade followed by Negishi cross-coupling provides a convergent access to trisubstituted alkene peptide isosteres.

Scheme 4

Microwave-accelerated Stille coupling on stannane 29 leads to trisubstituted alkene isosteres 33.

Scheme 5

Fluorination of vinyl stannane 29 and trifluoromethylation of vinyl iodide 36 provides fluoro and trifluoromethyl alkene amide bond isosteres.

Scheme 6

Preparation of cyclopropane dipeptide isostere building blocks.

Scheme 7

Preparation of the disubstituted cyclopropane-containing ΔPhg building block 61.

Scheme 8

Preparation of the trisubstituted cyclopropane-containing αMeΔPhg 67.

Scheme 9

Preparation of the l-Leu(ψ[(E)-C(CF₃)=CH])-d-Phe segment.

Scheme 10

Synthesis of cyclo[(Val-Orn-Leu-ψ[(E)-C(CF₃)=CH]-d-Phe-Pro-)₂].

Scheme 11

Synthesis of cyclo[(Val-Orn-Leu-ψ[(E)-C(CH₃)=CH]-d-Phe-Pro-)₂].

Scheme 12

Synthesis of cyclo[(Val-Orn-Leu-ψ[(Z)-C(F)=CH]-d-Phe-Pro-)₂].

Scheme 13

Synthesis of the GS analog cyclo[(Val-Orn-Leu-ψ[(E)-CH=CH]-d-Phe-Pro-)₂].

Scheme 14

Synthesis of a GS segment 112 with a trisubstituted alkene amide bond replacement at d-Phe-Pro.

Scheme 15

Synthesis of a GS analog 116 with a trisubstituted alkene amide bond replacement in the d-Phe-Pro β-turn sequence.

Scheme 16

Synthesis of XJB-5-131. The agent contains an ROS/RNS scavenger (red), a conformationally preorganized mitochondrial targeting unit (blue/black), and a peptide isostere motif that decreases N-terminal exopeptidase degradation (black).