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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., The recent advances in accelerated polymerization of N-carboxyanhydrides (NCAs) enrich the toolbox to prepare well-defined polypeptide materials. Here the authors use crown ethers to catalyze the polymerization of NCA initiated by conventional primary amine initiators in solvents with low polarity and low hydrogen-bonding ability.

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., A highly membrane-penetrative cell-penetrating polypeptide-antibiotic conjugate (VPP-G) was developed to efficiently eradicate intracellular bacteria both in vitro and in vivo via a dual mechanism

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 synthe...

Polypeptides with trigger-responsive helix–coil transition behaviours are interesting biomaterials due to their helix-specific assemblies and biomedical performances. Based on the pH-sensitive, conformationally switchable triazole polypeptides, we reported the manipulation of the helix–coil transition profile, which was determined by the combined molecular interactions of triazole and other side-chain functionalities. Specifically, the introduction of side-chain hydrophobic moieties or hydrogen bonding acceptors neutralized the helix-disrupting effect of side-chain triazoles, which altered the pH-responsive conformational transition profile of the polypeptides. These results inspired us to design new triazole polypeptides bearing dimethylamino side chains, which exhibited interesting helix–coil–helix transition behaviours as the pH decreased.

Multiblock copolypeptides have attracted broad interests because their potential to form ordered structures and possess protein-mimetic functions. Controlled synthesis of multiblock copolypeptides ...

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.

With PEG-like properties, such as hydrophilicity and stealth effect against protein absorption, oligo(ethylene glycol) (OEG)-functionalized polypeptides have emerged as a new class of biomaterials alternative to PEG with polypeptide-like properties. Synthesis of this class of materials, however, has been demonstrated very challenging, as the synthesis and purification of OEG-functionalized N-carboxyanhydrides (OEG-NCAs) in high purity, which is critical for the success in polymerization, is tedious and often results in low yield. OEG-functionalized polypeptides are therefore only accessible to a few limited labs with expertise in this specialized NCA chemistry and materials. Here, we report the controlled synthesis of OEG-functionalized polypeptides in high yield directly from the OEG-functionalized amino acids via easy and reproducible polymerization of non-purified OEG-NCAs. The prepared amphiphilic block copolypeptides can self-assemble into narrowly dispersed nanoparticles in water, which show properties suitable for drug delivery applications.

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.

The recent outbreaks of infectious diseases caused by multidrug-resistant pathogens have sounded a piercing alarm for the need of new effective antimicrobial agents to guard public health. Among different types of candidates, antimicrobial peptides (AMPs) and the synthetic mimics of AMPs (SMAMPs) have attracted significant enthusiasm in the past thirty years, due to their unique membrane-active antimicrobial mechanism and broad-spectrum antimicrobial activity. The extensive research has brought many drug candidates into clinical and pre-clinical development. Despite tremendous progresses have been made, several major challenges inherent to current design strategies have slowed down the clinical translational development of AMPs and SMAMPs. However, these challenges also triggered many efforts to redesign and repurpose AMPs. In this review, we will first give an overview on AMPs and their synthetic mimics, and then discuss the current status of their clinical translation. Finally, the recent advances in redesign and repurposing AMPs and SMAMPs are highlighted.

Glatiramer acetate (GA), a linear random copolypeptide, is a first-line treatment for multiple sclerosis (MS). A major concern, however, is that GA treatment is associated with adverse effects and poor patient adherence due to the need for frequent injections. Here we describe improved performance of the polymeric drug, even at low doses with less-frequent injections, through the modification of its architecture into a star-shaped GA (sGA). In a sGA, multiple GAs are covalently linked onto a core, which greatly changes their properties such as molecular weight, size, and shape. The spherical sGA is retained longer in the body after intraperitoneal injection, and is more readily internalized by RAW 264.7 macrophage cells and bone marrow-derived dendritic cells than GA. In C57BL/6 mice induced with experimental autoimmune encephalitis, a mouse model for MS, sGA treatment exerts disease amelioration effect that is significantly better than that of GA despite a lower dose and less frequent injection. Moreover, spinal cord pathologies of demyelination and leukocyte infiltration are dramatically less pronounced in the sGA treatment condition compared to the GA treatment condition. Thus, we propose that sGA with a higher-ordered architecture offers an attractive and potentially viable treatment option for MS patients.

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.

Antibacterial peptides as a novel antimicrobial agent have overwhelmingly caught researchers’ attention with unique superiority. Here, we report a series of triblock copolypeptides K10-b-Fn-b-K10 synthesized by sequential NCA ring-opening polymerization. The obtained triblock copolypeptides have good antibacterial efficacy against both S. aureus and E. coli. The hemolysis test has been conducted and it suggests that the triblock copolypeptides have low cytotoxicity and good biocompatibility. Furthermore, we present a systematic study on their self-assembly behavior and confirm that they can self-assemble into vesicles. Hence, such triblock copolypeptides have potential applications in antibacterial therapy and biomedical application field.

The performance of non-viral gene delivery vehicles, especially cationic polymers, is often challenged by the multiple cellular barriers that pose inconsistent requirements for material properties. A most pronounced inconsistency is exemplified by the molecular weight (MW)-related transfection efficiency and cytotoxicity. In this study, we report the development of photo-degradable, branched poly(β-amino ester)s (BPAE-NB) to realize efficient and photo-controlled DNA and siRNA delivery. BPAE-NB possessing built-in light-responsive 2-nitrobenzene moieties in the polymer backbone was synthesized via the A2 (amine) + B3 (triacrylate) + C2 (diacrylate) polycondensation reaction from 4-amino-1-butanol (A2), trimethylolpropane triacrylate (B3), and (2-nitro-1,3-phenylene)bis(methylene) diacrylate (NPBMDA, C2). The highly branched BPAE-NB with the multivalent arrangement of cationic groups provides stronger nucleic acid binding capacity than its linear analogue LPAE-NB, and thus features stronger trans-membrane gene delivery capabilities and higher transfection efficiencies. Upon UV light irradiation, the backbone of BPAE-NB can quickly degrade into low-MW fragments as a consequence of the cleavage of the light-responsive 2-nitrobenzene, thus promoting intracellular gene release and diminishing the toxicity of materials at the post-transfection state. As such, in multiple mammalian cells, BPAE-NB exhibited remarkably higher DNA/siRNA transfection efficiency yet lower cytotoxicity than its non-responsive analogue BPAE-CC upon light irradiation, notably outperforming commercial reagents PEI 25k and Lipofectamine 2000. This study therefore provides an effective topology- and photo-controlled approach to precisely manipulate the transfection efficiency and toxicity of polycationic gene vectors, and may also provide promising additions to the existing non-viral gene delivery vectors.

A series of amphiphilic diblock copolypeptides (K30 -b-F15 , K30 -b-F30 , and K30 -b-F45 ) 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-1 and 2 μg mL-1 , 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.

The Nanxiong red-bed basin and its adjacent Zhuguang granite form a distinctive basin-mountain landform in the Nanling region, South China. Research results suggest that the Zhuguang granite is a polyphase composite pluton developed on the metamorphic basement of the paleo-Tethys-paleo-Asian tectonic regime and possesses geometrical and kinematic features of hot-doming extensional tectonics at the middle-upper crustal level, which is considered as a magmatic complex that resulted from the collision-orogeny during the Indosinian Period, the subduction-consuming during the Early Yanshanian Period and the intra-continental basaltic underplating and deep-seated geodynamics during the Late Yanshanian Period. The Nanxiong basin is a Late Cretaceous-Paleogene asymmetric faulted basin that is characterized by a fault boundary on the northern side and an uncomformable boundary on the southern side, its deposit center was migrated gradually from south to north. Structural kinematic results on the basin-mountain coupled zone demonstrate that the ductile and the brittle rheological layers show a quite coincident sense of shear, implying that it is a continuous process from the ductile extensional deformation followed by locally sinistral strike-slip shear at a middle-crustal level to the brittle tensional deformation at a upper-crustal level during formation of granitic doming extensional tectonics. The Zhuguang granite and the Nanxiong faulted basin constructed a semi-graben tectonic system. Lithological and geochemical results suggest that the Late Triassic to Jurassic granitic bodies in the Zhuguang have some similar features: high SiO 2 , Al 2 O 3 , K 2 O contents, alkalinity index > 2.8, ANKC value > 1.1, LREE-enriched pattern with high REE contents, marked negative Eu anomalies, enrichment in Rb and Th, depletion in Ba and Nb, showing a K-rich and Al-rich calc-alkaline affinity, which suggest a continuous magmatic evolution from Late Triassic to Jurassic. Formation of Nanxiong basin and evolution of basin-mountain system were controlled both by the Zhuguang granitic-doming and the regional extensional tectonics. Development of the olivine basalt in the basin suggests that tension action was very strong during lava eruption. The magma-type zircon grains of basalt from the Nanxiong basin yielded the SHRIMP age of 96±1Ma, providing reliable geochronological constraint on the tectono-thermal event and basin-mountain evolution in the Nanling region, South China.

Single zircon LAM-ICPMS U-Pb dating indicates that the Guidong granitic complex is a multistage batholith formed during Indosinian-Yanshanian time. The Luxi body (239 ±5 Ma) and the Xiazhuang body (235.8 ±7.6 Ma) intruded during Indosinian time, whereas the Aizi body (160.1 ±6.1 Ma) and the Siqian body (151 ±11 Ma) formed during Yanshanian time. Inherited zircons (1275–2137 Ma) in the Xiazhuang body imply that at least part of the source rocks of the Guidong complex are from the Proterozoic basement of southeast China. Detailed single zircon LAM-ICPMS U-Pb dating results provide important evidence for understanding the evolution, tectonic setting and mineralisation of the complex.

The large southern Zhuguangshan granitic batholith composite consists of granites with ages varying from the Caledonian through Indosinian to Yanshanian. Based on K-Ar dating data, the ages of the major parts of this composite were previously regarded as Yanshanian. In this study, the SHRIMP zircon U-Pb dating method has been adopted for six plutons, Ledong, Longhuashan, Dawozi, Zhaidi, Baiyun and Jiangnan, in the southern Zhuguangshan composite, in which the four plutons other than Baiyun and Jiangnan were previously regarded as Yanshanian granites. Magmatic zircons from these six plutons, dated by this study, have yielded ages of 239±5 Ma (MSWD = 2.5), 239±5 Ma (MSWD = 2.5), 239±2 Ma (MSWD = 1.7), 239±4 Ma (MSWD = 3.2), 231±2 Ma (MSWD = 0.81) and 231±3 Ma (MSWD = 1.8), respectively. The results indicate that these plutons were formed by early Indosinian magmatism. Geochemical characteristics suggest that these granites were formed in an extensional tectonic environment. Therefore, the Indosinian period granites in the southern Zhuguangshan composite were formed by partial melting of the Paleo-Mesoproterozoic crustal components during the collapse of thickened lithosphere after the collision between the South China and Indosinian plates.