The recent advances in accelerated polymerization of N-carboxyanhydrides (NCAs) enriched the toolbox to prepare well-defined polypeptide materials. Herein we report the use of crown ether (CE) to catalyze the polymerization of NCA initiated by conventional primary amine initiators in solvents with low polarity and low hydrogen-bonding ability. The cyclic structure of the CE played a crucial role in the catalysis, with 18-crown-6 enabling the fastest polymerization kinetics. The fast polymerization kinetics outpaced common side reactions, enabling the preparation of well-defined polypeptides using an α-helical macroinitiator. Experimental results as well as the simulation methods suggested that CE changed the binding geometry between NCA and propagating amino chain-end, which promoted the molecular interactions and lowered the activation energy for ring-opening reactions of NCAs. This work not only provides an efficient strategy to prepare well-defined polypeptides with functionalized C-termini, but also guides the design of catalysts for NCA polymerization.
Synthetic polypeptides, the analogues
of natural proteins, are
important biomaterials that have found broad biomedical applications.
Ring-opening polymerization of N-carboxyanhydrides
offers a reliable way to prepare high-molecular-weight polypeptides
in large scale with diverse side-chain functionalities. The past two
decades have seen significant advances in the polypeptide field, with
the development of various controlled polymerization methodologies,
the deeper understanding on secondary structures, and the discovery
of new assembly behaviors and applications. In this Perspective, we
highlight several key advances in the chemical synthesis and materials
application of synthetic polypeptides and discuss promising future
directions in this area.
Hydrogels that are injectable, self-healing, and multiresponsive are becoming increasingly relevant for a wide range of applications. In this work, we have successfully developed a novel approach in the fabrication of smart hydrogels with all the above properties. A symmetrical ABA triblock copolymer was first synthesized via atom transfer radical polymerization with a temperature responsive middle block and two permanently hydrophilic glycopolymer chains on both ends. Hydrogels were subsequently constructed by mixing the triblock copolymer with another linear hydrophilic copolymer bearing benzoxaborole groups. The interactions of the benzoxaborole groups with the sugar hydroxyl groups allowed the formation of dynamic covalent bonds. The resulting hydrogels exhibited temperature, pH, and sugar responsiveness. Rheological studies confirmed that the mechanical property can be tuned by changing the pH as well as the galactose/ benzoxaborole molar ratio. Furthermore, the hydrogels showed excellent self-healing ability and shear-thinning performance due to the inherent well-known dynamic covalent bonds of boronic esters. Therefore, these types of hydrogels can have excellent biomedical applications.
Multiblock
copolypeptides have attracted broad interests because
their potential to form ordered structures and possess protein-mimetic
functions. Controlled synthesis of multiblock copolypeptides through
the sequential addition of N-carboxyanhydrides (NCAs),
especially with the block number higher than five, however, is challenging
and rarely reported due to competing side reactions during the polymerization
process. Herein, we report the unprecedented synthesis of block copolypeptides
with up to 20 blocks, enabled by ultrafast polypeptide chain propagation
in a water/chloroform emulsion system that outpaces side reactions
and ensures high end-group fidelity. Well-defined multiblock copolypeptides
with desired block numbers, block lengths, and block sequences, as
well as very low dispersity were readily attainable in a few hours.
This method paves the way for the fast production of a large number
of sequence-regulated multiblock copolypeptide materials, which may
exhibit interesting assembly behaviors and biomedical applications.
Infections
by intracellular pathogens are difficult to treat because
of the poor accessibility of antibiotics to the pathogens encased
by host cell membranes. As such, a strategy that can improve the membrane
permeability of antibiotics would significantly increase their efficiency
against the intracellular pathogens. Here, we report the design of
an adaptive, metaphilic cell-penetrating polypeptide (CPP)–antibiotic
conjugate (VPP-G) that can effectively eradicate the intracellular
bacteria both
in vitro
and
in vivo
. VPP-G was synthesized by attaching vancomycin to a highly membrane-penetrative
guanidinium-functionalized metaphilic CPP. VPP-G effectively kills
not only extracellular but also far more challenging intracellular
pathogens, such as
S. aureus
, methicillin-resistant
S. aureus
, and vancomycin-resistant
Enterococci
. VPP-G enters the host cell via a unique metaphilic membrane penetration
mechanism and kills intracellular bacteria through disruption of both
cell wall biosynthesis and membrane integrity. This dual antimicrobial
mechanism of VPP-G prevents bacteria from developing drug resistance
and could also potentially kill dormant intracellular bacteria. VPP-G
effectively eradicates MRSA
in vivo
, significantly
outperforming vancomycin, which represents one of the most effective
intracellular antibacterial agents reported so far. This strategy
can be easily adapted to develop other conjugates against different
intracellular pathogens by attaching different antibiotics to these
highly membrane-penetrative metaphilic CPPs.
The application of synthetic polypeptides
is greatly limited by
the difficulty of the purification and polymerization of N-carboxyanhydrides (NCAs). Here, we report a streamlined, controlled
synthesis of polypeptides directly from amino acids, avoiding the
NCA purification, by adding small-molecular amine scavengers (AS)
in situ to efficiently eliminate the remaining organic impurities
in the emulsion polymerization system. Such a process enables controlled
synthesis of PEG-containing, homo, block, and random polypeptides
in a highly consistent manner under open-air condition, directly from
amino acid derivatives in various formats and independent of NCA preparation
methods.
A series of amphiphilic diblock copolypeptides (K -b-F , K -b-F , and K -b-F ) were synthesized via N-carboxy-α-amino-anhydride ring-opening polymerization. The copolypeptides had excellent antibacterial efficacy to both Gram positive (S. aureus) and Gram negative (E. coli) bacteria. The minimum inhibitory concentrations (MICs) against E. coli and S. aureus are 8 μg mL and 2 μg mL , respectively, lower than most natural and artificial antimicrobial peptides (AMPs). The morphological changes of the bacteria treated with diblock copolypeptides were investigated by transmission electron microscopy; the results proved that the diblock copolypeptides had a similar antibacterial pore-forming mechanism to natural cationic peptides. This was confirmed by laser scanning confocal microscope images. CCK-8 results and the MICs showed that the diblock copolypeptides have high selectivity to bacteria, which suggested that the diblock copolypeptides could be excellent candidates to replace traditional antibiotics in future.
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