Sang Min Lim

Metal-organic framework (MOF) films possess versatile chemical functionalities, intrinsic microporosity, and facile integration with surfaces and devices, generating significant interest across diverse fields. However, precise control over large-area MOF films with hierarchical micro- and macroporosity remains challenging because it is difficult to simultaneously maintain multiscale porosity, structural integrity, and film uniformity. In this study, we developed a hydrophilic-lipophilic balance (HLB)-guided strategy for the self-assembly of hierarchical macroporous UiO-66 (Ce) films with well-defined bimodal pore structures. Systematic tuning of the total HLB (HLB_total) and surfactant architecture modulated the interfacial tension and mixed micelle behavior, yielding uniform hierarchical macroporous films at an HLB_total of 11. Dissipative particle dynamics (DPD) simulations further showed that differences in HLB among surfactants affect micellar miscibility and interfacial stability, thereby influencing micelle organization and structural evolution during film growth. The resulting hierarchical macroporous UiO-66 (Ce) films exhibited enhanced catalytic performance in glycerol acetalization, attributed to improved mass transport and an increased number of active sites. This study provides fundamental insights into HLB-guided self-assembly of hierarchical macroporous MOF films, thereby contributing to the rational design of advanced porous materials for catalytic and separation applications.

Fingolimod, the first nonselective S1P₁ modulator for multiple sclerosis (MS), is effective but linked to cardiovascular side effects. To improve the drug safety profile, we developed β-arrestin biased S1P₁ agonists with reduced G-protein activity using a pharmacophore-based approach. Among them, compound 28 showed 4.51-fold β-arrestin bias relative to fingolimod: (EC_{50(G-protein)}─12.7 nM and EC_{50(β-arrestin)}─3.23 nM) and strong S1P₁ selectivity and favorable drug-like properties. Docking studies suggested its β-arrestin bias is due to weaker interactions with TM3 (especially R120) and stronger TM7 interactions. During in vivo studies, compound 28 reduced peripheral lymphocyte counts to 24.4% of baseline and significantly improved the clinical scores in preventative and therapeutic experimental autoimmune encephalomyelitis mouse models. Cardiovascular safety was confirmed using human induced pluripotent stem cell-derived cardiomyocytes. These results highlight compound 28 as the first β-arrestin biased S1P₁ agonist with effective immunomodulatory activity and improved safety, offering a promising MS therapeutic candidate.

Tauopathy is characterized by the abnormal aggregation of tau proteins. In order to develop drugs for tauopathies, a variety of different therapeutic strategies have been investigated. Synapse loss is a hallmark of tauopathies and is reportedly related to cognitive impairment in Alzheimer's disease as well. Emerging evidence suggests that pathogenic tau species are linked to synaptic dysfunction and synapse loss in tauopathies. As such, a potential therapeutic approach to ameliorate synaptic dysfunction and counteract synaptic loss due to pathogenic tau holds promise. This review highlights the pathological links between tau pathology and synaptic integrity and current efforts to develop therapeutics rescuing synaptic dysfunction for tauopathies, which will help to understand the association between tau and synapses and develop disease‐modifying drugs for tauopathies.

Because of the wide use of Fingolimod for the treatment of multiple sclerosis (MS) and its cardiovascular side effects such as bradycardia, second-generation sphingosine 1-phosphate receptor 1 (S1P1) agonist drugs for MS have been developed and approved by FDA. The issue of bradycardia is still present with the new drugs, however, which necessitates further exploration of S1P1 agonists with improved safety profiles for next-generation MS drugs. Herein, we report a tetrahydroisoquinoline or a benzo[c]azepine core-based S1P1 agonists such as 32 and 60 after systematic examination of hydrophilic groups and cores. We investigated the binding modes of our representative compounds and their molecular interactions with S1P1 employing recent S1P1 cryo-EM structures. Also, favorable ADME properties of our compounds were shown. Furthermore, in vivo efficacy of our compounds was clearly demonstrated with PLC and EAE studies. Also, the preliminary in vitro cardiovascular safety of our compound was verified with human iPSC-derived cardiomyocytes.

The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline.

The tau protein is a highly soluble and natively unfolded protein. Under pathological conditions, tau undergoes multiple post-translational modifications (PTMs) and conformational changes to form insoluble filaments, which are the proteinaceous signatures of tauopathies. To dissect the crosstalk among tau PTMs during the aggregation process, we phosphorylated and ubiquitylated recombinant tau in vitro using GSK3β and CHIP, respectively. The resulting phospho–ub-tau contained conventional polyubiquitin chains with lysine 48 linkages, sufficient for proteasomal degradation, whereas unphosphorylated ub-tau species retained only one–three ubiquitin moieties. Mass-spectrometric analysis of in vitro reconstituted phospho–ub-tau revealed seven additional ubiquitylation sites, some of which are known to stabilize tau protofilament stacking in the human brain with tauopathy. When the ubiquitylation reaction was prolonged, phospho–ub-tau transformed into insoluble hyperubiquitylated tau species featuring fibrillar morphology and in vitro seeding activity. We developed a small-molecule inhibitor of CHIP through biophysical screening; this effectively suppressed tau ubiquitylation in vitro and delayed its aggregation in cultured cells including primary cultured neurons. Our biochemical findings point to a “multiple-hit model,” where sequential events of tau phosphorylation and hyperubiquitylation function as a key driver of the fibrillization process, thus indicating that targeting tau ubiquitylation may be an effective strategy to alleviate the course of tauopathies.

Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-β (Aβ) induced mitochondrial dysfunction and in acute and transgenic Alzheimer’s disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aβ-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.

Significance: The ubiquitin–proteasome system and autophagy are two major intracellular proteolytic pathways, and both remove misfolded and proteotoxic proteins from eukaryotic cells. This study describes the detailed regulatory pathway of proteasome degradation by autophagy for its own quality control. We discovered that a portion of inhibited proteasomes is actively sequestered into the aggresome, an insoluble fraction of the mammalian cell. The aggresome functions as a triage point for proteasome recovery and autophagic degradation. This mainly distinguishes proteasome quality control in mammals from that in other organisms. STUB1/CHIP E3 Ub ligase has a critical role in targeting inhibited proteasomes into the aggresome. These results provide strong insights into protein catabolism in various pathological conditions originating from impaired proteasomes.