Modulation of Conformational Transition of Polypeptides under Slightly Acidic Environment^†

Abstract

Comprehensive Summary Controlling the conformational transition of polypeptides under slightly acidic environment is challenging. Herein, we report a class of pH‐responsive helix‐to‐coil conformationally transitionable polypeptides (pCTPs) by simply conjugating tertiary amine groups (TAs) to polylysine. Their conformation is highly dependent on the charge state of TAs, showing a helical structure when most TAs are deprotonated and a non‐helical structure when majority of TAs are protonated. The conformational transition pH can be modulated by tuning the hydrophobicity of TAs and the incorporation of hydrophobic monomers at a pH range of 7.2 to 6.0. Such pCTP showed a vesicle‐to‐micelle transition when their conformation transformed from helix to coil, facilitating controlled drug release. Our study provided an approach to control the conformational transition of polypeptides under slightly acidic condition.

Recent Progress of pH-Responsive Peptides, Polypeptides, and Their Supramolecular Assemblies for Biomedical Applications

“…This property allows polypeptides to specifically target cells in tissues with lower extracellular pH. 84,85 The glycopeptides designed by Schlaad et al formed an α-helix under acidic conditions (pH 3.5). 86 The α-helix was stable and resistant to degradation, and once formed, it had good water solubility, making it suitable for drug delivery systems.…”

“…Xiong et al reported a class of pH-responsive polypeptides (pCTP) capable of transitioning from a α-helical to a coiled conformation. 84 When the conformation of pCTP changes from α-helix to coil, it exhibits a transformation from vesicles to micelles, serving as an intelligent carrier for controlled drug release. This study provided a method to control the conformational transition of polypeptides under mildly acidic conditions, which can be used as a tool for targeted delivery of drugs or imaging probes to tissues with low extracellular pH.…”

“…These are achieved by integrating additional functional sequences into the modular framework of the AM1 peptide, enhancing their functionality and application scope. 84,88 3.1.2. β-Sheet. The β-sheet is another common secondary structure in polypeptide molecules, characterized by a sheetlike formation through either parallel (referred to as parallel βfolding) or antiparallel (referred to as antiparallel β-folding) arrangements of polypeptide segments.…”

Conformation-Switchable Polypeptides as Molecular Gates for Controllable Drug Release

“…31−37 Additionally, amphiphilic polypeptides with αhelical hydrophobic segments tend to self-assemble into vesicles due to the parallel arrangement of rigid helices, while their β-sheet and random-coiled analogues are more likely to form micelles. 20,22,38 Due to the distinct differences of materials properties between helical and random-coiled conformation, conformation-switchable polypeptides are designed and synthesized to manipulate their biomedical functions in situ. The transition of secondary structures is achieved through the fine-tuning of side-chain interactions including electrostatic interactions, 39−42 polarity, 43−47 hydrogen bonds, 48 coordination interaction, 49 and base-pairing interactions, 50 which activates or deactivates the helixassociated functions under desired conditions.…”

“…Synthetic polypeptides have displayed great potentials in the biomedical field and are regarded as promising candidates for the design of drug carriers due to their desired biocompatibility and biodegradability. − As protein mimics, polypeptides can adopt ordered secondary structures (e.g., α-helix and β-sheet) through hydrogen bonding interactions between backbone peptide bonds, − which endow them with conformation-specific assembly behaviors and biomedical functions. − For instance, cationic polypeptides with α-helical structures exhibit much higher membrane-penetrating activity than their random-coiled analogues, which are internalized through the “pore-formation” mechanism. − Through proper side-chain design, α-helical, cationic polypeptides have been widely studied to promote the intracellular delivery of molecular cargos or to facilitate the design of antimicrobial or antitumor polymers. − Additionally, amphiphilic polypeptides with α-helical hydrophobic segments tend to self-assemble into vesicles due to the parallel arrangement of rigid helices, while their β-sheet and random-coiled analogues are more likely to form micelles. ,, Due to the distinct differences of materials properties between helical and random-coiled conformation, conformation-switchable polypeptides are designed and synthesized to manipulate their biomedical functions in situ . The transition of secondary structures is achieved through the fine-tuning of side-chain interactions including electrostatic interactions, − polarity, − hydrogen bonds, coordination interaction, and base-pairing interactions, which activates or deactivates the helix-associated functions under desired conditions.…”