Yihui Xie

One-bead-one-compound (OBOC) DNA-encoded library (DEL) enables high-throughput activity-based screening to find novel hits against pharmaceutical targets. Herein, we developed solid-phase and DNA-compatible conditions to implement the three-component Van Leusen reaction (imidazole formation) for OBOC DELs. High-throughput validation was conducted (employing every potential building block) to simultaneously provide the groundwork for potential library synthesis and demonstrate the reagent scope. A total of 251 aldehydes, 380 amines, and 19 tosylmethyl isocyanides (TosMICs) were validated, with 65 aldehydes, 194 amines, and 15 TosMICs meeting the 50% yield cutoff. We take particular interest in aliphatic TosMICs because they yield more drug-like products. Encouragingly, aliphatic TosMICs perform well in solid-phase, but not solution-phase.

Here, we report a new class of peptidomimetic macrocycles with well‐defined three‐dimensional structures and low conformational flexibility. They are assembled from fused‐ring spiro‐ladder oligomers (spiroligomers) by modular solid‐phase synthesis. Two‐dimensional nuclear magnetic resonance confirms their shape persistency. Triangular macrocycles of tunable sizes assemble into membranes with atomically precise pores, which exhibit size and shape‐dependent molecular sieving towards a series of structurally similar compounds. The exceptional structural diversity and stability of spiroligomer‐based macrocycles will be explored for more applications.

Here, we report a new class of peptidomimetic macrocycles with well‐defined three‐dimensional structures and low conformational flexibility. They are assembled from fused‐ring spiro‐ladder oligomers (spiroligomers) by modular solid‐phase synthesis. Two‐dimensional nuclear magnetic resonance confirms their shape persistency. Triangular macrocycles of tunable sizes assemble into membranes with atomically precise pores, which exhibit size and shape‐dependent molecular sieving towards a series of structurally similar compounds. The exceptional structural diversity and stability of spiroligomer‐based macrocycles will be explored for more applications.

Drug delivery systems are designed to control the release rate and location of therapeutic agents in the body to achieve enhanced drug efficacy and to mitigate adverse side effects. In particular, drug-releasing implants provide sustained and localized release. We report nanostructured polymer monoliths synthesized by polymerization-induced microphase separation (PIMS) as potential implantable delivery devices. As a model system, free poly(ethylene oxide) homopolymers were incorporated into the nanoscopic poly(ethylene oxide) domains contained within a cross-linked polystyrene matrix. The in vitro release of these poly(ethylene oxide) molecules from monoliths was investigated as a function of poly(ethylene oxide) loading and molar mass as well as the molar mass and weight fraction of poly(ethylene oxide) macro-chain transfer agent used in the PIMS process for forming the monoliths. We also developed nanostructured microneedles targeting efficient and long-term transdermal drug delivery by combining PIMS and microfabrication techniques. Finally, given the prominence of poly(lactide) in drug delivery devices, the degradation rate of microphase-separated poly(lactide) in PIMS monoliths was evaluated and compared with bulk poly(lactide).

We combine self-assembly in solution, complexation with metallic salts and phase separation induced by solvent–non-solvent exchange to prepare nanostructured membranes for separation in the nanofiltration range. This method was applied to prepare membranes from newly synthesized poly(acrylic acid)-b-polysulfone-b-poly(acrylic acid) copolymers dissolved in a selective solvent mixture and immersed in aqueous Cu²⁺ or Ag⁺ solutions.

Biofouling impedes the performance of membrane bioreactors. In this study, we investigated the antifouling effects of polysulfone membranes that were modified by 1,2,3-triazole and palladium (Pd) nanoparticles. The modified membranes were evaluated for antibacterial and antifouling efficacy in a monoculture species biofilm (i.e., drip flow biofilm reactor, DFR) and mixed species biofilm experiment (i.e., aerobic membrane reactor, AeMBR). 1,2,3-triazole and Pd nanoparticles inhibited growth of Pseudomonas aeruginosa in both aerobic and anaerobic conditions. The decrease in bacterial growth was observed along with a decrease in the amount of total polysaccharide within the monoculture species biofilm matrix. When the modified membranes were connected to AeMBR, the increase in transmembrane pressure was lower than that of the non-modified membranes. This was accompanied by a decrease in protein and polysaccharide concentrations within the mixed species biofilm matrix. Biomass amount in the biofilm layer was also lower in the presence of modified membranes and there was no detrimental effect on the performance of the reactor as evaluated from the nutrient removal rates. 16S rRNA analysis further attributed the delay in membrane fouling to the decrease in relative abundance of selected bacterial groups. These observations collectively point to a lower fouling occurrence achieved by the modified membranes.

For the first time, self-assembly and non-solvent induced phase separation was applied to polysulfone-based linear block copolymers, reaching mechanical stability much higher than other block copolymer membranes used in this method, which were mainly based on polystyrene blocks. Poly(tert-butyl acrylate)-b-polysulfone-b-poly(tert-butyl acrylate) (PtBA_30k-b-PSU_14k-b-PtBA_30k) with a low polydispersity of 1.4 was synthesized by combining step-growth condensation and RAFT polymerization. Various advanced electron microscopies revealed that PtBA_30k-b-PSU_14k-b-PtBA_30k assembles into worm-like cylindrical micelles in DMAc and adopts a “flower-like” arrangement with the PSU central block forming the shell. Computational modeling described the mechanism of micelle formation and morphological transition. Asymmetric nanostructured membranes were obtained with a highly porous interconnected skin layer and a sublayer with finger-like macrovoids. Ultrafiltration tests confirmed a water permeance of 555 L m⁻² h⁻¹ bar⁻¹ with a molecular weight cut-off of 28 kg mol⁻¹. PtBA segments on the membrane surface were then hydrolyzed and complexed with metals, leading to cross-linking and enhancement of antibacterial capability.