Crosslinked Aspartic Acids as Helix‐Nucleating Templates

Abstract

Described is a facile helix-nucleating template based on a tethered aspartic acid at the N-terminus [terminal aspartic acid (TD)]. The nucleating effect of the template is subtly influenced by the substituent at the end of the side-chain-end tether as indicated by circular dichroism, nuclear magnetic resonance, and molecular dynamics simulations. Unlike most nucleating strategies, the N-terminal amine is preserved, thus enabling further modification. Peptidomimetic estrogen receptor modulators (PERMs) constructed using this strategy show improved therapeutic properties. The current strategy can be regarded as a good complement to existing helix-stabilizing methods.

The peptide PROTAC modality: a novel strategy for targeted protein ubiquitination

“…To maintain α-helical structure and specificity of protein epitope mimetic in short peptide, they reserved consensus pentapeptide motif, and developed a series of helix-stabilized cyclic peptides as selective inhibitors to bind ER tightly and selectively by regulating ER-coactivator interactions. Inspired by these peptidomimetic estrogen receptor modulators (PERMs), Li et al 30 further used the N-terminal aspartic acid cross-linking strategy (terminal aspartic acid, TD) to design more stabilized peptide modulators (TD-PERMs) with good cell permeability. Then, they 31 conjugated TD-PERMs with the recruiting peptide of the Von Hippel-Lindau (VHL) E3 ligase to form a p-PROTAC molecule with enhanced biological activity compared to TD-PERMs.…”

“…As the classic methods for inhibiting ERα, modulation of the conformational state of ERα with various unnatural ligands often causes drug resistance in breast cancer patients 85 - 87 . In the previous reported PROTAC, Zhao et al 30 used the N-terminal aspartic acid to promote formation of helical structures to enhance the stability and cell permeability, which helped the TD strategy-based PROTAC to form a complex with E3 ubiquitin ligase for effective degradation of ERα and inhibition of estrogen-positive breast cancer cell 31 . It is worth noting that TD strategy-based p-PTOTAC targeted the different sites of the POI compared with the small molecules PROTAC, and this study proved the successful application of stabilized peptides based PROTAC and its prospects.…”

“…One vital issue is the retention time of the protein epitope mimetic conformation, especially for the short peptides. It is conformational flexibility that causes poor stability and cell permeability of peptides, thereby making intracellular targets inaccessible by originally fragile and hydrophilic peptides 30 . Hence, conformational constraint of peptides with unnatural backbone structure provides promising method to solve the previous problems 102 - 103 .…”

Cell-Penetrating Peptides: Design Strategies beyond Primary Structure and Amphipathicity

“…Recently, N-terminal crosslinking of aspartic acid has been reported to stabilize the helical structure [ 149 ]. The crosslinking was obtained by simple peptide bond formation between the side chain of the terminal aspartic acid and the amino group of the 2,3-diaminopropionic acid (Dap) to obtain a crosslink that shows a similar distance to that introduced through stapling [ 150 ]. This method was optimized for pentapeptides, and cyclization using l - and d -stereoisomers of aspartic acid was assessed.…”

Twists or turns: stabilising alpha vs. beta turns in tetrapeptides

“…Cyclic tetrapeptides with D-rather than L-residues at the (i) position X were better helix nucleators (17 vs. 5, 18 vs. 13). Cyclic tetrapeptides Ac-[(isoD or d)AADap]-NH 2 (21 or 22) 10 and cyclic pentapeptide 25 6e have been reported previously. We nd that they were better nucleators than 17 and 18.…”