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  1. Abstract

    Macrocycles are unique molecular structures extensively used in the design of catalysts, therapeutics and supramolecular assemblies. Among all reactions reported to date, systems that can produce macrocycles in high yield under high reaction concentrations are rare. Here we report the use of dynamic hindered urea bond (HUB) for the construction of urea macrocycles with very high efficiency. Mixing of equal molar diisocyanate and hindered diamine leads to formation of macrocycles with discrete structures in nearly quantitative yields under high concentration of reactants. The bulkyN-tert-butyl plays key roles to facilitate the formation of macrocycles, providing not only the kinetic control due to the formation of the cyclization-promotingcisC = O/tert-butyl conformation, but also possibly the thermodynamic stabilization of macrocycles with weak association interactions. The bulkyN-tert-butyl can be readily removed by acid to eliminate the dynamicity of HUB and stabilize the macrocycle structures.

     
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  2. Abstract

    The recent advances in accelerated polymerization ofN-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.

     
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  3. Abstract

    Enzymes provide optimal three-dimensional structures for substrate binding and the subsequent accelerated reaction. Such folding-dependent catalytic behaviors, however, are seldom mechanistically explored with reduced structural complexity. Here, we demonstrate that the α-helix, a much simpler structural motif of enzyme, can facilitate its own growth through the self-catalyzed polymerization ofN-carboxyanhydride (NCA) in dichloromethane. The reversible binding between the N terminus of α-helical polypeptides and NCAs promotes rate acceleration of the subsequent ring-opening reaction. A two-stage, Michaelis–Menten-type kinetic model is proposed by considering the binding and reaction between the propagating helical chains and the monomers, and is successfully utilized to predict the molecular weights and molecular-weight distributions of the resulting polymers. This work elucidates the mechanism of helix-induced, enzyme-mimetic catalysis, emphasizes the importance of solvent choice in the discovery of new reaction type, and provides a route for rapid production of well-defined synthetic polypeptides by taking advantage of self-accelerated ring-opening polymerizations.

     
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  6. Systemic, non-viral siRNA delivery for cancer treatment is mainly achieved via condensation by cationic materials ( e.g. , lipids and cationic polymers), which nevertheless, suffers from poor serum stability, non-specific tissue interaction, and unsatisfactory membrane activity against efficient in vivo gene knockdown. Here, we report the design of a metastable, cancer-targeting siRNA delivery system based on two functional polymers, PVBLG-8, a cationic, helical cell-penetrating polypeptide, and poly( l -glutamic acid) (PLG), an anionic random-coiled polypeptide. PVBLG-8 with rigid, linear structure showed weak siRNA condensation capability, and PLG with flexible chains was incorporated as a stabilizer which provided sufficient molecular entanglement with PVBLG-8 to encapsulate the siRNA within the polymeric network. The obtained PVBLG-8/siRNA/PLG nanoparticles (PSP NPs) with positive charges were sequentially coated with additional amount of PLG, which reversed the surface charge from positive to negative to yield the metastable PVBLG-8/siRNA/PLG@PLG (PSPP) NPs. The PSPP NPs featured desired serum stability during circulation to enhance tumor accumulation via the enhanced permeability and retention (EPR) effect. Upon acidification in the tumor extracellular microenvironment and intracellular endosomes, the partial protonation of PLG on PSPP NPs surface would lead to dissociation of PLG coating from NPs, exposure of the highly membrane-active PVBLG-8, and surface charge reversal from negative to positive, which subsequently promoted tumor penetration, selective cancer cell internalization, and efficient endolysosomal escape. When siRNA against epidermal growth factor receptor (EGFR) was encapsulated, the PSPP NPs showed excellent tumor penetration capability, tumor cell uptake level, EGFR silencing efficiency, and tumor growth inhibition efficacy in U-87 MG glioblastoma tumor spheroids in vitro and in xenograft tumor-bearing mice in vivo , outperforming the PSP NPs and several commercial reagents such as Lipofectamine 2000 and poly( l -lysine) (PLL). This study therefore demonstrates a facile and unique design approach of metastable and charge reversal NPs, which overcomes multiple biological barriers against systemic siRNA delivery toward anti-cancer treatment. 
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  7. Synthetic polypeptides derived from the ring-opening polymerization of N -carboxyanhydrides can spontaneously fold into stable secondary structures under specific environmental conditions. These secondary structures and their dynamic transitions play an important role in regulating the properties of polypeptides in self-assembly, catalysis, polymerization, and biomedical applications. Here, we review the current strategies to modulate the secondary structures, and highlight the conformation-specific dynamic properties of synthetic polypeptides and the corresponding materials. A number of mechanistic studies elucidating the role of secondary structures are discussed, aiming to provide insights into the new designs and applications of synthetic polypeptides. We aim for this article to bring to people's attention synthetic polymers with ordered conformations, which may exhibit association behaviors and material properties that are otherwise not found in polymers without stable secondary structures. 
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