Rational Design of MMP Degradable Peptide-Based Supramolecular Filaments

Abstract

One-dimensional nanostructures formed by self-assembly of small molecule peptides have been extensively explored for use as biomaterials in various biomedical contexts. However, unlike individual peptides that can be designed to be specifically degradable by enzymes/proteases of interest, their self-assembled nanostructures, particularly those rich in β-sheets, are generally resistant to enzymatic degradation because the specific cleavage sites are often embedded inside the nanostructures. We report here on the rational design of β-sheet rich supramolecular filaments that can specifically dissociate into less stable micellar assemblies and monomers upon treatment with matrix metalloproteases-2 (MMP-2). Through linkage of an oligoproline segment to an amyloid-derived peptide sequence, we first synthesized an amphiphilic peptide that can undergo a rapid morphological transition in response to pH variations. We then used MMP-2 specific peptide substrates as multivalent cross-linkers to covalently fix the amyloid-like filaments in the self-assembled state at pH 4.5. Our results show that the cross-linked filaments are stable at pH 7.5 but gradually break down into much shorter filaments upon cleavage of the peptidic cross-linkers by MMP-2. We believe that the reported work presents a new design platform for the creation of amyloid-like supramolecular filaments responsive to enzymatic degradation.

Designed supramolecular filamentous peptides: balance of nanostructure, cytotoxicity and antimicrobial activity

“…More recently, peptide nanofilaments and nanobeacons were shown to have different enzymatic degradation rates. 15 Consistent with this recent discovery, our results demonstrate that the supramolecular assembly can be used as another effective approach to improve the protease susceptibilities of antimicrobial peptides containing naturally occurring α-amino acids. As shown in Figure 3, peptides without enzymatic treatment were eluted as a major singlet at ~17 mins.…”

Multi-responsive hydrogels derived from the self-assembly of tethered allyl-functionalized racemic oligopeptides

“…4.67 Å was described in a variety of β -sheet forming peptides as a characteristic hydrogen bonding length in the conformation of β- sheet secondary structures. 37, 54, 55 This WAXS signal overlapped with the 120 reflection of monoclinic PEG crystals, 49 which together with the signal corresponding to a d spacing of 3.86 Å correlated well with the crystallization and melting peaks in the DSC trace (Fig. S3).…”

Peptide–drug conjugates as effective prodrug strategies for targeted delivery

“…In recent years, increasing attention has been also paid to enzyme-sensitive drug delivery systems due to the typically high specificity towards substrates associated with this approach [141–144]. Early research focused on using enzymes in a similar fashion to other methods of stimulus applied in drug delivery systems [9], to induce morphology change or disassembly of nanocarriers, resulting in the release of a payload.…”