Peptide fibrils as monomer storage of the covalent HIV‐1 integrase inhibitor

Abstract

We have recently reported the covalent inhibition of HIV-1 integrase by an N-terminal succinimide-modified lens epithelium-derived growth factor (361-370) peptide. We also showed that this peptide is proteolytically stable. Here, we show that this inhibitor is stored as fibrils that serve as a stock for the inhibitory monomers. The fibrils increase the local concentration of the peptide at the target protein. When the monomers bind integrase, the equilibrium between the fibrils and their monomers shifts towards the formation of peptide monomers. The combination of fibril formation and subsequent proteolytic stability of the peptide may bring to new strategy for developing therapeutic agents. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

Interactions Between Peptide Assemblies and Proteins for Medicine

“…Reches and co-workers have successfully applied this approach to inhibit HIV-1 integrase (Figure 2), whereby the target enzyme can shift the equilibrium from the fibril to the active monomer. [21] The same concept can be further extended to other morphologies and active principles. As an example, spherical particles of self-assembling peptides could be loaded with small molecules to deliver them within cells.…”

“…In this regard, self‐association of bioactive peptides has been envisioned as an interesting strategy to provide a depot for their long‐term release to overcome such limitations. Reches and co‐workers have successfully applied this approach to inhibit HIV‐1 integrase (Figure 2), whereby the target enzyme can shift the equilibrium from the fibril to the active monomer [21] . The same concept can be further extended to other morphologies and active principles.…”

“…Oligomerization equilibrium is shifted by HIV‐1 integrase (IN) towards disassembly into active monomers that inhibit the enzyme. Reproduced with permission, Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd [21] …”

“…Interactions between short-peptide hydrogels and proteins have also been explored for the delivery of therapeutic Reproduced from ACS Nano 2021, [13] under a CC license. [21] proteins. Proteins are complex molecules to stabilize, due to their large size and three-dimensional structure.…”