Molecular Self-Assembly and Supramolecular Chemistry of Cyclic Peptides

Abstract

This Review focuses on the establishment and development of self-assemblies governed by the supramolecular interactions between cyclic peptides. The Review first describes the type of cyclic peptides able to assemble into tubular structures to form supramolecular cyclic peptide nanotubes. A range of cyclic peptides have been identified to have such properties, including α-peptides, β-peptides, α,γ-peptides, and peptides based on δ- and ε-amino acids. The Review covers the design and functionalization of these cyclic peptides and expands to a recent advance in the design and application of these materials through their conjugation to polymer chains to generate cyclic peptide-polymer conjugates nanostructures. The Review, then, concentrates on the challenges in characterizing these systems and presents an overview of the various analytical and characterization techniques used to date. This overview concludes with a critical survey of the various applications of the nanomaterials obtained from supramolecular cyclic peptide nanotubes, with a focus on biological and medical applications, ranging from ion channels and membrane insertion to antibacterial materials, anticancer drug delivery, gene delivery, and antiviral applications.

Figure 1

Examples of multiple-hydrogen-bonding arrays: (a) triple-hydrogen-bonding, (b) quadruple-hydrogen-bonding, (c) sextuple-hydrogen-bonding, (d) β-Sheet structure of a protein, and (e) double helix structure of DNA (the dashed lines in orange represent intermolecular hydrogen bonds, while the dashed lines in blue represent intramolecular hydrogen bonds).

Figure 2

Classes of cyclic peptides that assemble into SCPNs through hydrogen bonds: (a) cyclic α-alt(d,l)-peptide 1, (b) cyclic β-peptide 2, (c) cyclic α,γ-peptide 3, and (d) cyclic peptide containing ε-amino acids 4.

Figure 3

(a) Chemical structure of the cyclic α-alt(d,l)-peptide 5. (b) Schematic representation of the SCPN emphasizing the antiparallel stacking and the extensive network of intermolecular hydrogen-bonding interactions.

Figure 4

Representative chemical structures of cyclic α-alt(d,l)-peptides containing 8, 10, and 12 amino acids 6–8.

Figure 5

Proposed model for the sequential 1D-to-2D self-assembly of cyclic peptide 9. (a) Chemical structure of cyclic peptide 9.(b) Formation of amphiphilic nanotubes based on the multiple hydrogen-bonding interactions between the peptide rings.(c) Formation of 2D nanosheet assembly by the amphiphilic nanotubes. Reproduced with permission from ref (32). Copyright 2020 American Chemical Society.

Figure 6

Chemical structures of cyclic peptides 10 and 11 and crystal structures of their SCNPs. Reproduced with permission from ref (34). Copyright 2017 The Royal Society of Chemistry.

Figure 7

Chemical structures of cyclic peptides 12 and 13 and the proposed layered structure of enantiomers. Reproduced with permission from ref (35). Copyright 2004 American Chemical Society.

Figure 8

(a) Schematic representation of the chemical structure of cyclic peptide 14 and the cylindrical dimeric ensemble. (b) Crystal structure of the cylindrical dimeric ensemble. Reproduced with permission from ref (37). Copyright 1995 John Wiley and Sons.

Figure 9

Schematic representation showing the two N-methylated cyclic peptides 15 and 16 and the corresponding parallel and antiparallel ensembles. Reproduced with permission from ref (38). Copyright 1995 John Wiley and Sons.

Figure 10

(a) Chemical structure of the cyclic peptide 17 and schematic of the cyclic peptide fiber. (b) Molecular dynamics simulation. (c) Nanoindentation and bending experiments. Reproduced with permission from ref (40). Copyright 2015 American Chemical Society.

Figure 11

Chemical and crystal structures of the three stereoisomeric cyclic β-tetrapeptides 18–20. Reproduced with permission from ref (49). Copyright 1997 John Wiley and Sons.

Figure 12

(a) Chemical structures of the three cyclic β-tetrapeptides 21–23. (b) Predicted tubular structure with a parallel arrangement, showing a macrodipole along the nanotube. Reproduced with permission from ref (50). Copyright 1998 American Chemical Society.

Figure 13

Chemical structures of cyclic β-peptides 24-26 containing 3-, 4-, and 6-acetylated β-glycosamino acid units.

Figure 14

Schematic representation showing the formation of a SCNP by a cyclic α,γ-peptide 27 and the dimeric ensembles by two N-methylated cyclic peptides 28 and 29 via two different hydrogen bonding patterns. Reproduced with permission from ref (56). Copyright 2003 American Chemical Society.

Figure 15

Structures of the two N-methylated cyclic α,γ-peptides 30 and 31, and the corresponding dimers via parallel or antiparallel interactions. Reproduced with permission from ref (57). Copyright 1995 John Wiley and Sons.

Figure 16

Representative structures of cyclic α,γ-peptides 32–35 composed of 4, 6, 8, 10, and 12 amino acids. Reproduced with permission from ref (62). Copyright 2007 The Royal Society of Chemistry.

Figure 17

(a) Schematic representation of homo- and heterodimerization of the two Ach- and Acp-based cyclic α,γ-peptides 37 and 38. (b) Crystal structures of the two homodimers and the heterodimer. Reproduced with permission from ref (63). Copyright 2005 John Wiley and Sons.

Figure 18

(a) Chemical structures of the cyclic hexapeptide 39 and the corresponding dimer. (b) Crystal structures of the dimeric ensemble containing a Xe atom in the intradimer cavity. Reproduced with permission from ref (64). Copyright 2019 John Wiley and Sons.

Figure 19

(a) Chemical structure of the cyclic octapeptide 40. (b) Two possible structures of the SCNP. Reproduced with permission from ref (67). Copyright 2009 American Chemical Society.

Figure 20

Schematic representation showing the design of cyclic α,γ-peptide 42 and cyclic 3α,γ-peptide 43 from cyclic α-alt(d,l)-peptide 41 and the α- and γ-amino acid equivalence.

Figure 21

(a) Chemical structure of a single γ-amino acid-substituted cyclic peptide 44. (b) Chemical structures of cyclic peptides 45–47 composed by only γ-amino acids.

Figure 22

Structures of the two N-methylated cyclic d,l-α,δ-peptides 48 and 49, and the corresponding dimers via either parallel or antiparallel interactions. Reproduced with permission from ref (57). Copyright 2020 John Wiley and Sons.

Figure 23

(a) Chemical structure of the cyclic d,l-α,δ-peptide 50. (b) Side and top views of a computer-assisted model of C₆₀ encapsulated in the inner cavity of SCPN. (c) AFM topography micrographs from aqueous solutions of cyclic peptide 50 and C₆₀ deposited over mica and AFM height profiles along the transects. (d) STEM image of an aqueous solution of cyclic peptide 50 and C₆₀ after deposition on a holey carbon grid (scale bar 100 nm). Reproduced with permission from ref (80). Copyright 2018 The Royal Society of Chemistry.

Figure 24

Examples of cyclic peptides 51–54 containing ε-amino acids.

Figure 25

Schematic representation showing the synthesis of cyclic peptides via cyclization on resin and cyclization in solution methods.

Figure 26

(a) Chemical structure of the cyclic octapeptide 55 with two hydroxyl groups in its cavity. (b) Chemical structures of the pyridine-modified cyclic octapeptide 56 and the dimeric ensemble. (c) Computational structure of the dimeric ensemble showing the incorporation of the silver ion (gray color) within the dimer cavity coordinating the two picolinates (orange). (d) Chemical structure of the cyclic decapeptide 57. Reproduced with permission from ref (92). Copyright 2016 The Royal Society of Chemistry.

Figure 27

(a) Chemical structure of the pyrene-modified cyclic peptide 58 and its assembly. (b) Plausible model showing the formation of SWCNT/SCPN hybrids. (c) Plausible model showing the formation of silver cluster/SCPN hybrids. Reproduced with permission from refs ( and 109). Copyright 2014 and 2015 American Chemical Society.

Figure 28

Design strategies to construct heterodimers.

Figure 29

(a) Chemical structures of the C₆₀- and exTTF-containing cyclic peptides 65 and 66. (b) Formation of the heterodimer which brings C₆₀ in close proximity to exTTF. Reproduced with permission from ref (114). Copyright 2007 National Academy of Sciences.

Figure 30

(a) Chemical structure of a cyclic peptide–polymer conjugate 67. (b) Schematic representation of the self-assembled structure of the cyclic peptide–polymer conjugate. Reproduced with permission from ref (123). Copyright 2011 The Royal Society of Chemistry.

Figure 31

Schematic illustration of two synthetic methods for cyclic peptide–polymer conjugates.

Figure 32

(a) Chemical structures of the one- (68), two- (69), and three-arm (70) CP–PEG conjugates. (b) Aggregation number of the three conjugates in several solvents. (c) Contour plots of the degree of aggregation as a function of the hydrogen bond capacity and solvent polarity. Reproduced with permission from ref (139). Copyright 2018 The Royal Society of Chemistry.

Figure 33

(a) Scheme of the synthesis of dye-modified cyclic peptide–polymer conjugates 71 and 73 and control conjugate 72. (b) Schematic description of the FRET occurring between the donor (Cy3) and acceptor (Cy5) dyes in SCPPNs. (c) Evolution of normalized FRET ratio of the mixed system in DMF, water, and toluene as a function of time. Reproduced with permission from ref (136). Copyright 2018 John Wiley and Sons.

Figure 34

(a) Chemical structures of dye-functionalized cyclic peptide–diblock polymer conjugates 74 and 75. (b) Structure of the SCPPN formed by the cyclic peptide–diblock polymer conjugate. (c) Scheme showing no FRET occurring in a stable nondynamic system. (d) Scheme showing FRET occurring in a dynamic system. Reproduced with permission from ref (141) and available under a CC BY 4.0 License (http://creativecommons.org/licenses/by/4.0/).

Figure 35

Chemical structure of the asymmetric cyclic peptide–polymer conjugate pBA-CP-pPEGA 78 and its self-assembled tubisome structure in water. Reproduced with permission from ref (133). Copyright 2018 John Wiley and Sons.

Figure 36

(a) Schematic description of cyclic peptide–polymer conjugates bearing cleavable linkers and reduction-induced membrane interaction. (b) Synthesis of pEtOx bearing either cleavable or noncleavable linkers. (c) Synthesis of the stimuli-responsive and nonresponsive conjugates. Reproduced with permission from ref (153). Copyright 2019 The Royal Society of Chemistry.

Figure 37

(a) Schematic representation of the reversible self-assembly of a cyclic peptide–polymer conjugate via host–guest chemistry. (b) Chemical structures of the cyclic peptide–polymer conjugate Phe₂-CP-PEG 81, CB[7], and ADA. Reproduced with permission from ref (130). Copyright 2019 The Royal Society of Chemistry.

Figure 38

(a) TEM image of the PEG-CP-Cy3 conjugate 71 stained with UOAc against nanotubular length (b) and diameter (c) distributions extracted from the TEM images. Reproduced with permission from ref (136). Copyright 2017 John Wiley and Sons.

Figure 39

(a) Chemical structure of conjugate 82. AFM images of (b) a spin-casted THF solution of conjugate 82, (c) the conjugate solution after solvent-annealing and quenching, and (d) the conjugate solution following thermal annealing at 80 °C for 1 h and slow cooling. Reproduced with permission from ref (70). Copyright 2011 American Chemical Society.

Figure 40

STORM images of conjugates 74 and 75 showing their assembly mechanism following (a) premixing and (b) coinjection. Reproduced with permission from ref (141) and available under a CC BY 4.0 License (http://creativecommons.org/licenses/by/4.0/).

Figure 41

(a) Chemical structures of cyclic peptide 83 and 84 found to function as pH-responsive low-molecular weight gelators; (b) SAXS data and fits of supramolecular gels formed by 83 and 84. Reproduced with permission from ref (42). Copyright 2018 John Wiley and Sons.

Figure 42

(a) Chemical structures of 85, 86, and 87 investigated using GISAXS. (b) Unit cell structure of 85, self-assembled at the air–water interface. (c) Self-assembled structure of 86 at the air–water interface. Overlay shows the unit cell as determined by GISAXS. Reproduced with permission from ref (183). Copyright 1999 American Chemical Society.

Figure 43

Example SANS data demonstrating the influence of solvent polarity on the self-assembly of conjugate 68. Reproduced with permission from ref (139). Copyright 2018 The Royal Society of Chemistry.

Figure 44

(a) Chemical structure of PEG-CP–S-S-pPEGA (88) and a schematic representation of the redox-responsive self-assembly. (b) SANS data and fits corresponding to 88 before and after exposure to reducing agent demonstrating redox-responsive self-assembly. Reproduced with permission from ref (137). Copyright 2019 American Chemical Society.

Figure 45

SANS data and fits of tubisomes formed by pBA-CP-pPEGA with differing ratios of hydrophobic and hydrophilic polymer chain lengths. Reproduced with permission from ref (134). Copyright 2019 The Royal Society of Chemistry.

Figure 46

SEC traces of an unconjugated linear PEG alongside unimeric CP–PEG conjugates having one (68), two (69), or three (70) linear polymer arms. Reproduced with permission from ref (139). Copyright 2018 The Royal Society of Chemistry.

Figure 47

(a) Chemical structure of conjugate 89. (b) AF₄ fractogram of 89 with signals from MALS^90°– RI detectors, solvent: 0.1 M NaCl + 0.02% NaN₃.

Figure 48

Chemical structures of two cyclic peptides 142 and 143 modeled by Claro et al. and illustration of the parallel conformation in which they are thought to lay in regard to membrane surfaces. Reproduced with permission from ref (211). Copyright 2020 Elsevier.

Figure 49

(a) Chemical structure of the drug-loaded cyclic peptide–polymer conjugate 154. (b) Scheme of the nanotube loaded with organometallic drug RAPTA-C. Reproduced with permission from ref (131). Copyright 2014 John Wiley and Sons.

Figure 50

Cytotoxicity profile for the iridium drug-loaded conjugate 156 compared with free drug and drug-bearing polymer 155 (a) and the antiproliferative effects on cancerous cells vs healthy cells (b), which suggest a favorable selectivity index. Reproduced with permission from ref (173). Copyright 2018 American Chemical Society.

Figure 51

Confocal microscopy imaging as evidence of the intracellular localization of rhodamine labeled nanotubes in the lysosomal compartments of human PC3 cells. Reproduced with permission from ref (158). Copyright 2018 Elsevier.

Figure 52

Chemical structure of asymmetric conjugate 157 and the trigger responsive assembly into tubisomes which can successfully deliver anticancer drug doxorubicin into cells. Reproduced with permission from ref (132). Copyright 2020 John Wiley and Sons.

Figure 53

Pharmacokinetic profile comparing the overall plasma concentration of conjugate (156) vs equivalent free polymer (155) in vivo, indicating that nanotubes are cleared less rapidly and remain in circulation at a high concentration for longer. Reproduced with permission from ref (158). Copyright 2018 Elsevier.

Figure 54

Chemical structure of the cationic cyclic octapeptide 158 and illustration of the assembling cationic nanotubes binding ctDNA and the process of fluorescent labeling with GFP to track cellular uptake and transfection efficiencies. Reproduced with permission from ref (222). Copyright 2015 John Wiley and Sons.

Figure 55

Ex vivo bioluminescence imaging of mice organs after oral administration of pCMV-hRluc: cyclo-[(d-Trp-l-Tyr)₄-] nanotubes for 48 h (kidney) or 72 h (stomach, duodenum, liver). Reproduced with permission from ref (223). Copyright 2012 American Chemical Society.

Figure 56

Illustration of the proposed mechanism of action for peptides 161–171 during the early phases of adenovirus infection cycle. In the absence of peptide (a), viral material is taken up via clathrin-mediated endocytosis, and the acidic environment can allow disassembly and escape. Administration of peptide (b) prevents the formation of an acidic endosomal environment and therefore limits the escape of the virus. Reproduced with permission from ref (226). Copyright 2005 Elsevier.

Figure 57

Imaging to demonstrate the growth of HCV in the Huh-7 cell line for a DMSO control treatment (strong immunofluorescence) and the successful suppression of the virus upon incubation with peptides 182 and 183. Reproduced with permission from ref (227). Copyright 2011 Elsevier.