Liangren Zhang

To overcome the side effects of conduction block and QT prolongation associated with antiatrial fibrillation (AF) drug dronedarone, a novel class of dual IKr and late sodium current (late INa) inhibitors was developed through computational modeling, chemical modification, and electrophysiological screening. Lead compound 8b retained potent IKr inhibition (IC50 = 1.5 μM) comparable to dronedarone. Crucially, 8b avoided dronedarone’s peak INa inhibition while enhancing late INa suppression (IC50 = 2.5 μM) to counteract excessive QT prolongation and avoid conduction block. Compound 8b exhibited favorable pharmacokinetic properties (T1/2 = 5.02 h, F = 110% in mice, p.o.) and high ion channel selectivity. In an ex vivo rabbit heart model of AF, 8b demonstrated antiarrhythmic efficacy. Furthermore, 8b was effective in treating doxorubicin-induced heart failure in mice, a condition where dronedarone shows no therapeutic benefit. Collectively, 8b could serve as a potential new class III antiarrhythmic candidate.

The clinical management of invasive aspergillosis (IA) is limited by the scarcity of antifungal agents and the emergence and spread of drug resistance, which impairs therapeutic efficacy and poses a significant public health threat. Olorofim, a first-in-class clinical antifungal targeting dihydroorotate dehydrogenase (DHODH), represents a promising therapeutic option for IA. It shows activity against several filamentous fungi, including Aspergillus spp., both in vitro and in vivo . Olorofim-resistant Aspergillus fumigatus isolates, characterized by various amino acid substitutions (with a hotspot at G119), have been generated under laboratory conditions through olorofim exposure. However, the potential olorofim resistance mechanisms in Aspergillus flavus , the second-most common pathogen causing IA globally, remain entirely unexplored. In this study, we revealed that the residue G118 in A. flavus , conserved in many filamentous fungi, is homologous to G119 in A. fumigatus by DHODH amino acid sequence alignment. Using a CRISPR-based point mutation approach, we further confirmed that substitutions at the DHODH G118 residue confer acquired olorofim resistance in A. flavus . Additionally, we established a Galleria mellonella infection model and observed that these resistant isolates exhibited no obvious fitness cost, and olorofim treatment was ineffective against infections caused by DHODH G118 mutants. Molecular docking models further indicated that substitutions at the G118 locus may introduce steric hindrance, reducing the binding affinity between olorofim and the DHODH active site and thereby driving resistance. IMPORTANCE: Invasive aspergillosis, a life-threatening infection in immunocompromised patients, is increasingly difficult to treat due to limited antifungal options and rising resistance. Olorofim, a novel antifungal targeting dihydroorotate dehydrogenase (DHODH), represents a promising therapy. While resistance in Aspergillus fumigatus has been linked to DHODH G119 mutations, the mechanisms in the globally prevalent pathogen Aspergillus flavus remained unknown. Using CRISPR-based mutagenesis, we demonstrate that amino acid substitutions at G118 confer olorofim resistance, supported by molecular docking showing reduced drug binding. Importantly, olorofim failed to protect larvae infected with resistant mutants in an infection model. These findings provide essential insights for proactively monitoring and managing olorofim resistance in Aspergillus flavus , aiding clinical and public health responses. This study is registered with ClinicalTrials.gov as NCT05101187 and NCT06969703 .

Nuclear receptor-binding SET domain protein 3 (NSD3) is a histone H3K36 methyltransferase implicated in lung squamous cell carcinoma, yet chemical targeting is challenging due to the shallow PWWP reader pocket. Here, we report XSY12, a hydrophobic-tag degrader of the NSD3 PWWP domain that enables cellular NSD3 depletion (DC50 = 2.21 μM; Dmax = 80.2%). AI-guided discovery using a 3D fingerprinting platform (TF3P) identified a new NSD3–PWWP chemotype, which was optimized via deep learning–based molecular generation to the high-affinity ligand SYC2 (KD = 0.07 μM) and subsequently converted into XSY12. XSY12 promotes proteasome-dependent NSD3 depletion accompanied by HSP90-associated signatures, reduces H3K36 methylation, and induces apoptosis and G2/M arrest in NSD3-dependent models. In vivo, XSY12 achieved measurable exposure and significant tumor growth inhibition in an LUSC xenograft model at 100 mg/kg with acceptable tolerability. Collectively, these results provide a practical workflow linking AI-guided ligand discovery to functional degrader development.

Polo-like kinase 1 (PLK1) is a validated cancer therapeutic target, but ATP-competitive PLK1 inhibitors have been limited by dose-limiting toxicities. Here, we designed covalent inhibitors that specifically engage the noncatalytic Cys67 residue of the ATP domain. Rational optimization of the warhead and core scaffold led to B9 as a highly potent lead candidate. B9 exhibited low nanomolar enzymatic inhibition and exceptional cellular potency (IC50 = 0.4 nM in K562 leukemia cells), representing a >150-fold improvement over the reversible reference compound BI2536 (61 nM). B9 also showed favorable overall selectivity against nonrelated kinases. Remarkably, B9 achieved 77.6% oral bioavailability in mice. In an orthotopic K562 leukemia xenograft model, oral administration of B9 significantly suppressed the bioluminescence of leukemia burden and extended survival rates to 100% over 42 days without observable toxicity. These findings underscore the potential of B9 as a safe, orally bioavailable, and highly potent PLK1 inhibitor for preclinical development.

Activation of extrasynaptic δ-GABA_ARs represents a promising strategy for rapid-acting antidepressant therapy in major depressive disorder (MDD). Here, we report the discovery and pharmacological characterization of a novel series of thiazolo[4,5-d]pyrimidin-7(6H)-one derivatives as potent positive allosteric modulators selective for δ-GABA_ARs. Systematic SAR exploration identified compound 12i as a lead candidate, which demonstrated high potency on the extrasynaptic receptor subtype (α4β3δ: 950% current enhancement at 10 μM, EC₅₀ = 0.8 μM) while maintaining favorable modulation of synaptic subtypes. In vivo, 12i exerted rapid-acting antidepressant effects in both the mouse tail suspension test and the chronic restraint stress-induced depression model, with no addictive behaviors observed. These effects were completely abolished in δ-subunit knockout mice, confirming target engagement. Furthermore, 12i significantly enhanced NREM sleep in a p-chlorophenylalanine-induced insomnia model, highlighting potential dual efficacy in MDD with comorbid sleep disturbance. Collectively, these findings position 12i as a promising clinical candidate for next-generation rapid-acting antidepressant therapy.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is implicated in organophosphate (OP) poisoning, but the scarcity of potent and subtype-selective small-molecule antagonists has hindered the development of related therapeutic strategies. Based on previous structure–activity relationship (SAR) studies, 43 novel piperidine-spirooxadiazole derivatives were designed, synthesized and evaluated using patch-clamp electrophysiology. Two optimized compounds, Y9 and YZ4, exhibited submicromolar inhibition of α7 nAChR and demonstrated high subtype-selectivity for α7 over other nAChR and muscarinic acetylcholine receptor (mAChR) subtypes. They showed robust neuroprotective effects against paraoxon (POX)-induced cytotoxicity in vitro. Notably, YZ4 displayed favorable pharmacokinetic (PK) profiles, including high oral bioavailability and excellent brain penetration. In a POX-intoxicated mouse model, YZ4 significantly improved survival rates, alleviated seizure severity and mitigated multiorgan injury. These findings demonstrate YZ4 as a promising molecular tool for probing α7 nAChR pathophysiology and a potential therapeutic candidate for OP poisoning.

Marine natural products (MNPs) are a diverse group of bioactive compounds with varied chemical structures, but their biological origins are often misannotated due to complex host–microbe symbiosis. Propagated through public databases, such errors hinder biosynthetic studies and AI-driven drug discovery. Here, we develop a structure-based workflow of origin classification and misannotation correction for marine datasets. Using CMNPD and NPAtlas compounds, we integrate a two-step cleaning strategy that detects label inconsistencies and filters structural outliers with a microbial-pretrained graph neural network. The optimized model achieves a balanced accuracy of 85.56% and identifies 3996 compounds whose predicted microbial origins contradict their Animalia labels. These putative symbiotic metabolites cluster within known high-risk taxa, and interpretability analysis reveal biologically coherent structural patterns. This framework provides a scalable quality-control approach for natural product databases and supports more accurate biosynthetic gene cluster (BGC) tracing, host selection, and AI-driven marine natural product discovery.

C-Jun N-terminal kinase 3 (JNK3), a member of the mitogen-activated protein kinase (MAPK) family, is selectively enriched in the brain. It plays a significant role in the pathogenesis of neurodegenerative disorders, glaucoma, amyotrophic lateral sclerosis, and cancer, which makes it a promising drug target. However, the advancement of JNK3 inhibitors has been challenged by limited isoform selectivity. This article explains the pathway regulated by JNK3 and the unique functions of JNK3. A detailed structural analysis of JNK3 complexes with ligands is presented to uncover the molecular basis of binding interactions. The inhibitors are systematically classified according to their chemical scaffolds, and the reason for their isoform selectivity was discussed, providing a structural rationale for the evolution of JNK3 inhibitor design. The perspective concludes with an exploration of the challenges in the discovery of selective JNK3 inhibitors and proposes innovative strategies to surmount these obstacles.

N-Methyl-d-aspartate receptors (NMDARs) are extensively distributed throughout the central nervous system (CNS), and their dysfunction is implicated in depressive disorder. Positive allosteric modulators (PAMs) enhance the receptor's sensitivity and activity to agonists without direct activation. In this study, using structure-based virtual screening and artificial intelligence (AI)-assisted optimization, we identified Y36, a benzene-substituted piperidinol derivative and potent GluN2A-selective PAM. Y36 showed higher efficacy (E_max = 397.7%) than GNE-3419 (E_max = 196.4%), reducing the EC₅₀ values and increasing the E_max values for glutamate/glycine at GluN2A receptor. In chronic restraint stress (CRS) mice, Y36 significantly alleviated depression-related behaviors in multiple behavioral assessments, highlighting its superior antidepressant effects. Preliminary studies also confirmed favorable pharmacokinetic (PK) profiles and blood-brain barrier (BBB) penetration for Y36, with no signs of addiction, weight gain, or organ and tissue damage in mice. These results suggest that Y36 offers promising potential as a novel antidepressant with multiple antidepressant-like properties.