Peptide amphiphile

Peptide amphiphiles (PAs) are peptide-based molecules that self-assemble into supramolecular nanostructures including; spherical micelles, twisted ribbons, and high-aspect-ratio nanofibers.[1][2] A peptide amphiphile typically comprises a hydrophilic peptide sequence attached to a lipid tail, i.e. a hydrophobic alkyl chain with 10 to 16 carbons.[3] Therefore, they can be considered a type of lipopeptide.[1] A special type of PA, is constituted by alternating charged and neutral residues, in a repeated pattern, such as RADA16-I.[1] The PAs were developed in the 1990s and the early 2000s and could be used in various medical areas including: nanocarriers, nanodrugs, and imaging agents. However, perhaps their main potential is in regenerative medicine to culture and deliver cells and growth factors.[4]

History

Peptide amphiphiles were developed in the 1990s. They were first described by the group of Matthew Tirrell in 1995.[5][6] These first reported PA molecules were composed of two domains: one of lipophilic character and another of hydrophilic properties, which allowed self-assembly into sphere-like supramolecular structures as a result of the association of the lipophilic domains away from the solvent (hydrophobic effect), which resulted in the core of the nanostructure. The hydrophilic residues become exposed to the water, giving rise to a soluble nanostructure.

Work in the laboratory of Samuel I. Stupp by Hartgerink et al., in the early 2000s, reported a new type of PA that can self-assemble into elongated nanostructures. These novel PAs contain three regions: a hydrophobic tail, a region of beta-sheet-forming amino acids, and a charged peptide epitope designed to allow solubility of the molecule in water.[7][8] In addition, the PAs may contain a targeting or signaling epitope that allows the formed nanostructures to perform a biological function, either targeting or signaling, by interacting with living systems.[9][10] The self-assembly mechanism of these PAs is a combination of hydrogen-bonding between beta-sheet forming amino acids and hydrophobic collapse of the tails to yield the formation of cylindrical micelles that present the peptide epitope at extremely high density at the nanofiber surface. By changing pH or adding counterions to screen the charged surfaces of fibers, gels can be formed. It has been shown that injection of peptide amphiphile solutions in vivo leads to in situ gel formation due to the presence of counterions in physiological solutions. This, along with the complete biodegradability of the materials, suggests numerous applications in in vitro and in vivo therapies.

Applications

The modular nature of the chemistry allows the tuning of both the mechanical properties and bioactivities of the resulting self-assembled fibers and gels. Bioactive sequences can be used to bind growth factors to localize and present them at high densities to cells, or to directly mimic the function of endogenous biomolecules. Epitopes mimicking the adhesive RGD loop in fibronectin, the IKVAV sequence in laminin and a consensus sequence to bind heparin sulfate are just a few of the large library of sequences that have been synthesized. These molecules and the materials made from them have been shown to be effective in promoting cell adhesion, wound healing, mineralization of bone, differentiation of cells and even recovery of function after spinal cord injury in mice.

In addition to this, peptide amphiphiles can be used to form more sophisticated architectures which can be tuned on demand. In recent years, two discoveries have yielded bioactive materials with more advanced structures and potential applications. In one study, a thermal treatment of peptide amphiphile solutions led to the formation of large birefringent domains in the material that could be aligned by a weak shear force into one continuous monodomain gel of aligned nanofibers. The low shear forces used in aligning the material permit the encapsulation of living cells inside these aligned gels and suggest several applications in regenerating tissues that rely on cell polarity and alignment for function. In another study, the combination of positively charged peptide amphiphiles and negatively charged long biopolymers led to the formation of hierarchically ordered membranes. When the two solutions are brought into contact, electrostatic complexation between the components of each solution creates a diffusion barrier that prevents the mixing of the solutions. Over time, an osmotic pressure difference drives the reptation of polymer chains through the diffusion barrier into the peptide amphiphile compartment, leading to the formation of fibers perpendicular to the interface that grow over time. These materials can be made in the form of flat membranes or as spherical sacs by dropping one solution into the other. These materials are robust enough to handle mechanically and a range of mechanical properties can be accessed by altering growth conditions and time. They can incorporate bioactive peptide amphiphiles, encapsulate cells and biomolecules, and are biocompatible and biodegradable.

See also

References
  1. Hamley, I. W. (18 April 2011). "Self-assembly of amphiphilic peptides" (PDF). Soft Matter. 7 (9): 4122–4138. Bibcode:2011SMat....7.4122H. doi:10.1039/C0SM01218A. ISSN 1744-6848.
  2. Dehsorkhi, Ashkan; Castelletto, Valeria; Hamley, Ian W. (2014). "Self-assembling amphiphilic peptides". Journal of Peptide Science. 20 (7): 453–467. doi:10.1002/psc.2633. ISSN 1099-1387. PMC 4237179. PMID 24729276.
  3. Hamley, Ian W. (2015). "Lipopeptides: from self-assembly to bioactivity". Chemical Communications. 51 (41): 8574–8583. doi:10.1039/C5CC01535A. ISSN 1364-548X. PMID 25797909.
  4. Rubert Pérez, Charles M.; Stephanopoulos, Nicholas; Sur, Shantanu; Lee, Sungsoo S.; Newcomb, Christina; Stupp, Samuel I. (March 2015). "The Powerful Functions of Peptide-Based Bioactive Matrices for Regenerative Medicine". Annals of Biomedical Engineering. 43 (3): 501–514. doi:10.1007/s10439-014-1166-6. ISSN 0090-6964. PMC 4380550. PMID 25366903.
  5. Yu, Ying-Ching; Berndt, Peter; Tirrell, Matthew; Fields, Gregg B. (1 January 1996). "Self-Assembling Amphiphiles for Construction of Protein Molecular Architecture". Journal of the American Chemical Society. 118 (50): 12515–12520. doi:10.1021/ja9627656. ISSN 0002-7863.
  6. Berndt, Peter; Fields, Gregg B.; Tirrell, Matthew (1 September 1995). "Synthetic lipidation of peptides and amino acids: monolayer structure and properties". Journal of the American Chemical Society. 117 (37): 9515–9522. doi:10.1021/ja00142a019. ISSN 0002-7863.
  7. Hartgerink, J. D. (23 November 2001). "Self-Assembly and Mineralization of Peptide-Amphiphile Nanofibers". Science. 294 (5547): 1684–1688. Bibcode:2001Sci...294.1684H. doi:10.1126/science.1063187. OSTI 1531578. PMID 11721046. S2CID 19210828.
  8. Hartgerink, Jeffrey D.; Beniash, Elia; Stupp, Samuel I. (16 April 2002). "Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials". Proceedings of the National Academy of Sciences. 99 (8): 5133–5138. doi:10.1073/pnas.072699999. ISSN 0027-8424. PMC 122734. PMID 11929981.
  9. Cui, Honggang; Webber, Matthew J.; Stupp, Samuel I. (20 January 2010). "Self-assembly of peptide amphiphiles: From molecules to nanostructures to biomaterials". Biopolymers. 94 (1): 1–18. doi:10.1002/bip.21328. PMC 2921868. PMID 20091874.
  10. Hendricks, Mark P.; Sato, Kohei; Palmer, Liam C.; Stupp, Samuel I. (17 October 2017). "Supramolecular Assembly of Peptide Amphiphiles". Accounts of Chemical Research. 50 (10): 2440–2448. doi:10.1021/acs.accounts.7b00297. ISSN 0001-4842. PMC 5647873. PMID 28876055.
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