Amino Acid Pairing for De Novo Design of Self‐Assembling Peptides and Their Drug Delivery Potential

Abstract

Molecular self-assembly has emerged as the "bottom-up" engineering route to fabricate functional supramolecules for diverse applications. The design of molecular building units becomes critical in determining the structure, properties, and function of the resulting assemblies. Here, a de novo design principle of amino acid pairing (AAP) to generate new classes of self-assembling peptides (SAPs) is presented. In this study, the AAP focuses on hydrogen bonding, and ionic and hydrophobic interactions among amino acid pairs. With solely hydrogen bond pairs, SAPs can be constructed with only two amino acids. With all three AAP strategies (hydrogen bonds, ionic and hydrophobic pairs), a short novel SAP is constructed. This peptide can self-assemble into β -sheet-rich nanofi bers with a relatively low "critical aggregation concentration (CAC)" of ∼ 10 μ M . It also shows the ability to stabilize and deliver the hydrophobic anticancer agent ellipticine in aqueous solution. The peptide-drug complexes/co-assemblies exhibit anticancer activity against human lung carcinoma cells A549 and breast cancer cells MCF-7, and have good dilution stability. The presented AAP design provides a new strategy to fabricate functional supramolecules with potential applications in nanomedicine.

Self‐Assembling Peptides as Cell‐Interactive Scaffolds

“…However, modifying α-helical based self-assembling peptides without disrupting the self-assembly process poses greater difficulties, but noncovalent functionalization with peptide tags offers a possible route to rendering this class of peptide hydrogels bioactive. [91,92] It is also still a challenge to be able to design various molecules that assemble in a predictive manner to a wide range of desired structures, although rational design of supramolecular structures are steps toward that direction [93,94] In addition, while the use of self-assembling peptides have largely been limited to soft tissue engineering, the development of hydrid systems may offer an interesting avenue in expanding their application. Finally, solid-state synthesis of peptides may be efficient for small scale production, but its scale up can be expensive.…”

Recent advances in self-assembled peptides: Implications for targeted drug delivery and vaccine engineering

“…Here, the hydrophobic residues encapsulated and stabilised hydrophobic drugs and enhanced selfassociation of the peptide. Additionally, hydrogen bonds were found to stabilise peptide assemblies with charged residues, increasing the solubility of the peptide [87]. It has been shown that EAK16-II (AEAEAKAKAEAEAKAK) and EAK16-IV (AEAEAEAEAKAKAKAK) have different charge distributions creating stabilized hydrophobic compounds in aqueous solutions and releasing them into the cell in a controlled manner.…”

“…Hydrogel scaffold composed of alternating hydrophilic and hydrophobic residues and clusters of negative and positive charges on the N-and C-terminus, respectively. Adapted from [87].…”

“…This model used combinations of amino acid pairings that selfassembled through weak interactions, including hydrogen bonds, hydrophobic interactions and ionic bonds. For example, a peptide that contained the hydrogen bonding pair (Q-N), one ionic-complementary pair (E-K) and two hydrophobic residue pairs (F-F) [87]. The charge distribution along the backbone of this ionic-complementary peptide was a determining factor in its self-assembly conformation and nanostructured stability.…”

Arginine-rich ionic complementary peptides as potential drug carriers: Impact of peptide sequence on size, shape and cell specificity

“…30,31 In addition, the effects of altered peptide lengths (EAR16-II vs. EAR8-II), amino acid arrangements (EAR8-II vs. EAR8-IIa) and side chain hydrophobicity (EAR8-IIa vs. ELR8-IIa) were also investigated. These factors could have impacts on peptide self-assembly, peptide-EPT complexation and their surface properties, 32,33 which may lead to different delivery efficacy and biocompatibility. We explored in detail the relationship between sequence and structure/ property of the new peptides.…”