ACS Central Science最新文献

Computational generation of cyclic peptide inhibitors using machine learning models requires large size training data sets often difficult to generate experimentally. Here we demonstrated that sequential combination of Random Forest Regression with the pseudolikelihood maximization Direct Coupling Analysis method and Monte Carlo simulation can effectively enhance the design pipeline of cyclic peptide inhibitors of a tumor-associated protease even for small experimental data sets. Further in vitro studies showed that such in silico-evolved cyclic peptides are more potent than the best peptide inhibitors previously developed to this target. Crystal structure of the cyclic peptides in complex with the protease resembled those of protein complexes, with large interaction surfaces, constrained peptide backbones, and multiple inter- and intramolecular interactions, leading to good binding affinity and selectivity.

Combination of statistical and computational approaches enables rapid and cost-effective generation of potent cyclic peptide inhibitors of a human cancer associated protease.

Prodrug-based nanoassemblies are promising platforms for cancer therapy. Prodrugs typically consist of three main components: drug modules, intelligent response modules, and modification modules. However, the available modification modules are usually hydrophobic aliphatic side chains, which affect the activation efficiency of the prodrugs. Herein, hydrophilic ethylene glycol fragments were inserted between the modification modules and the response modules, and the important effects of hydrophilic fragments on the assembly, drug release, and therapeutic index of the prodrugs were investigated. Notably, the introduction of hydrophilic fragments affected the intermolecular forces of the prodrugs and increased the interaction of hydrogen bonding. In addition, hydrophilic fragments significantly improved the redox drug release profiles, which affected the therapeutic index of the prodrug nanoassemblies. PTX-SS-OA NPs with hydrophilic fragments exhibited increased redox sensitivity, enhanced cytotoxicity, and superior antitumor efficacy. In comparison, PTX-SS-OAL NPs without hydrophilic fragments showed limited redox sensitivity and cytotoxicity but displayed better safety. Overall, the hydrophilic fragment is a critical determinant in modulating the therapeutic index of the prodrug nanoassemblies, which contributes to the development of advanced prodrug nanodelivery systems.

Computational generation of cyclic peptide inhibitors using machine learning models requires large size training data sets often difficult to generate experimentally. Here we demonstrated that sequential combination of Random Forest Regression with the pseudolikelihood maximization Direct Coupling Analysis method and Monte Carlo simulation can effectively enhance the design pipeline of cyclic peptide inhibitors of a tumor-associated protease even for small experimental data sets. Further in vitro studies showed that such in silico-evolved cyclic peptides are more potent than the best peptide inhibitors previously developed to this target. Crystal structure of the cyclic peptides in complex with the protease resembled those of protein complexes, with large interaction surfaces, constrained peptide backbones, and multiple inter- and intramolecular interactions, leading to good binding affinity and selectivity.

Electron transporting (n-type) polymeric mixed conductors are an exciting class of materials for devices with aqueous electrolyte interfaces, such as bioelectronic sensors, actuators, and soft charge storage systems. However, their charge transport performance falls short of their p-type counterparts, primarily due to electrochemical side reactions such as the oxygen reduction reaction (ORR). To mitigate ORR, a common strategy in n-type organic semiconductor design focuses on lowering the lowest unoccupied molecular orbital (LUMO) level. Despite empirical observations suggesting a correlation between deep LUMO levels, low ORR, and enhanced electrochemical cycling stability in water, this relationship lacks robust evidence. In this work, we delve into the electrochemical reactions of n-type polymeric mixed conductors with varying LUMO levels and assess the impact of ORR on charge storage performance and organic electrochemical transistor (OECT) operation. Our results reveal a limited correlation between LUMO levels and ORR currents, as well as the electrochemical operational stability of the films. While ORR currents minimally contribute to OECT channel currents under fixed biasing conditions, n-type films self-discharge rapidly at floating potentials in a capacitor-like configuration. The density functional theory analysis, complemented by X-ray photoelectron spectroscopy, underscores the critical role of backbone chemistry in controlling O₂-related degradation pathways and device performance losses. These findings highlight the persistent challenge posed by ORR in n-type semiconductor design and advocate for shifting the focus toward exploring chemical moieties with limited O₂ interactions to enhance operational stability and performance at n-type film/water interfaces.

The onset of oxygen reduction reaction for n-type organic mixed ionic-electronic conductors closely aligns with their reduction onset and can hardly be mitigated by frontier energy level adjustment.

Electron transporting (n-type) polymeric mixed conductors are an exciting class of materials for devices with aqueous electrolyte interfaces, such as bioelectronic sensors, actuators, and soft charge storage systems. However, their charge transport performance falls short of their p-type counterparts, primarily due to electrochemical side reactions such as the oxygen reduction reaction (ORR). To mitigate ORR, a common strategy in n-type organic semiconductor design focuses on lowering the lowest unoccupied molecular orbital (LUMO) level. Despite empirical observations suggesting a correlation between deep LUMO levels, low ORR, and enhanced electrochemical cycling stability in water, this relationship lacks robust evidence. In this work, we delve into the electrochemical reactions of n-type polymeric mixed conductors with varying LUMO levels and assess the impact of ORR on charge storage performance and organic electrochemical transistor (OECT) operation. Our results reveal a limited correlation between LUMO levels and ORR currents, as well as the electrochemical operational stability of the films. While ORR currents minimally contribute to OECT channel currents under fixed biasing conditions, n-type films self-discharge rapidly at floating potentials in a capacitor-like configuration. The density functional theory analysis, complemented by X-ray photoelectron spectroscopy, underscores the critical role of backbone chemistry in controlling O₂-related degradation pathways and device performance losses. These findings highlight the persistent challenge posed by ORR in n-type semiconductor design and advocate for shifting the focus toward exploring chemical moieties with limited O₂ interactions to enhance operational stability and performance at n-type film/water interfaces.

Stretchable electronics have seen substantial development in skin-like mechanical properties and functionality thanks to the advancements made in intrinsically stretchable polymer electronic materials. Nanoscale phase separation of polymer materials within an elastic matrix to form one-dimensional nanostructures, namely nanoconfinement, effectively reduces conformational disorders that have long impeded charge transport properties of conjugated polymers. Nanoconfinement results in enhanced charge transport and the addition of skin-like properties. In this Outlook, we highlight the current understanding of structure-property relationships for intrinsically stretchable electronic materials with a focus on the nanoconfinement strategy as a promising approach to incorporate skin-like properties and other functionalities without compromising charge transport. We outline emerging directions and challenges for intrinsically stretchable electronic materials with the aim of constructing skin-like electronic systems.

Stretchable electronics have seen substantial development in skin-like mechanical properties and functionality thanks to the advancements made in intrinsically stretchable polymer electronic materials. Nanoscale phase separation of polymer materials within an elastic matrix to form one-dimensional nanostructures, namely nanoconfinement, effectively reduces conformational disorders that have long impeded charge transport properties of conjugated polymers. Nanoconfinement results in enhanced charge transport and the addition of skin-like properties. In this Outlook, we highlight the current understanding of structure–property relationships for intrinsically stretchable electronic materials with a focus on the nanoconfinement strategy as a promising approach to incorporate skin-like properties and other functionalities without compromising charge transport. We outline emerging directions and challenges for intrinsically stretchable electronic materials with the aim of constructing skin-like electronic systems.

Nanoconfinement reduces conformational disorder in functional polymers, enhancing charge transport and enabling multiple skin-like properties through a tailored elastic matrix.

Herein, we report a visible-light-induced charge-transfer-complex-enabled dicarboxylation and deuterocarboxylation of C═C bonds with oxalate as a masked CO₂ source under catalyst-free conditions. In this reaction, we disclosed the first example that the tetrabutylammonium oxalate could be able to aggregate with aryl substrates via π–cation interactions to form the charge transfer complexes, which subsequently triggers the single electron transfer from the oxalic dianion to the ammonium countercation under irradiation of 450 nm bule LEDs, releasing CO₂ and CO₂ radical anions. Diverse alkenes, dienes, trienes, and indoles, including challenging trisubstituted olefins, underwent dicarboxylation and anti-Markovnikov deuterocarboxylation with high selectivity to access valuable 1,2- and 1,4-dicarboxylic acids as well as indoline-derived diacids and β-deuterocarboxylic acids under mild conditions. The in situ generated CO₂^•– and CO₂ molecules from oxalic radical anions could both add to the C═C bond without assistance of any photocatalyst or additives, which made this reaction sustainable, clean, and efficient.

Tetrabutylammonium oxalate (TBAO) works as a carboxylation reagent for 1,2-, 1,4-, and 1,6-difunctionalization of alkene, diene, and triene substrates in the absence of photocatalyst or any additives.

Herein, we report a visible-light-induced charge-transfer-complex-enabled dicarboxylation and deuterocarboxylation of C=C bonds with oxalate as a masked CO₂ source under catalyst-free conditions. In this reaction, we disclosed the first example that the tetrabutylammonium oxalate could be able to aggregate with aryl substrates via π-cation interactions to form the charge transfer complexes, which subsequently triggers the single electron transfer from the oxalic dianion to the ammonium countercation under irradiation of 450 nm bule LEDs, releasing CO₂ and CO₂ radical anions. Diverse alkenes, dienes, trienes, and indoles, including challenging trisubstituted olefins, underwent dicarboxylation and anti-Markovnikov deuterocarboxylation with high selectivity to access valuable 1,2- and 1,4-dicarboxylic acids as well as indoline-derived diacids and β-deuterocarboxylic acids under mild conditions. The in situ generated CO₂ ^•- and CO₂ molecules from oxalic radical anions could both add to the C=C bond without assistance of any photocatalyst or additives, which made this reaction sustainable, clean, and efficient.