Acta Pharmaceutica Sinica B

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Acquired pharmacoresistance in temporal lobe epilepsy is driven by Nav1.6-mediated subicular hyperexcitability

Acta Pharmaceutica Sinica B. 2026, 16(7): 4442-4458.

Pharmacoresistance to anti-seizure medications (ASMs) remains a major unmet challenge in temporal lobe epilepsy (TLE), and occurs diversely, as classified to primary or acquired manner. The pathophysiological underpinnings of acquired pharmacoresistance remain elusive. Here, using a hippocampal kindling mouse model, we established that prolonged lamotrigine (LTG) treatment—either during or after kindling—induces broad-spectrum resistance to multiple ASMs, effectively recapitulating clinical patterns of acquired pharmacoresistance. Multimodal interrogation revealed hyperexcitability of subicular pyramidal neurons as a critical factor in pharmacoresistance, characterized by elevated c-Fos expression specifically within the subiculum, as well as hyperexcitability of subicular glutamatergic pyramidal neurons. This hyperexcitability phenotype stemmed from Nav1.6 upregulation, driving both enhanced persistent sodium current (INaP) and a pro-excitatory shift in voltage-dependent activation kinetics of voltage-gated sodium channel (VGSC). Crucially, pharmacological activation of subicular Nav1.6 sufficed to induce acquired pharmacoresistance in pharmaco-responsive mice. Conversely, subiculum-specific Nav1.6 knockdown in pyramidal neurons (but not GABAergic neurons) prevented or reversed pharmacoresistance, while analogous genetic manipulation in the CA1 had no such impact. Chemogenetic inhibition of subicular pyramidal neurons (mimicking ASM effects) restored drug responsiveness, directly implicating compensatory increases in Nav1.6 offsetting ASM’s inhibitory function on subicular excitability in acquired pharmacoresistance. These findings collectively identify Nav1.6 upregulation in subicular pyramidal neurons as a critical driver of acquired pharmacoresistance in TLE, highlighting a novel therapeutic target for refractory epilepsy.
Scaffold hopping yields novel furo[3,2-d]pyrimidine NNRTIs with optimized antiviral potency, enhanced selectivity, and reduced hERG liability

Acta Pharmaceutica Sinica B. 2026, 16(7): 4459-4477.

Considering the exceptional anti-HIV-1 potency of rilpivirine (RPV) against diverse mutant strains and its remarkable human ether-a-go-go related gene (hERG) potassium channel inhibition (IC₅₀ = 0.50 μmol/L) as well as low selectivity (SI = 3989), a series of novel furo-[3,2-d]pyrimidine derivatives were rationally designed through a scaffold hopping strategy. Encouragingly, compound 10 revealed a striking reduction in hERG channel inhibition (IC₅₀ > 30 μmol/L) and significant increase in selectivity (SI = 161580). Notably, 10 exhibited excellent antiviral activity against various HIV-1 strains (EC₅₀ = 1.9-46.3 nmol/L). In particular, 10 displayed prominent inhibitory potency against Y188L (EC₅₀ = 15.5 nmol/L) and F227L + V106A strain (EC₅₀ = 8.7 nmol/L), which was superior to those of RPV (EC₅₀ ₍Y₁₈₈L₎ = 79.4 nmol/L, EC₅₀ ₍F₂₂₇L ₊ V₁₀₆A₎ = 81.6 nmol/L). Besides, no apparent cytotoxicity (CC₅₀ = 314.8 μmol/L) and negligible suppression of CYP isoenzymes were detected. Overall, these findings illustrated that 10 was a potentially promising NNRTI for HIV-1 therapy.
A novel NAMPT activator ameliorates obesity by repressing ACSL1-dependent lipid synthesis

Acta Pharmaceutica Sinica B. 2026, 16(7): 4478-4490.

Excessive incorporation of long-chain fatty acids (LCFAs) into triglycerides in adipose tissue is a key contributor to obesity and related metabolic disorders, and pharmacologically modulating this process remains challenging. Here, we synthesized a library of β-indoquinazolinone derivatives via palladium-catalyzed oxidative addition complex chemistry and identified compound b2b as a potent and selective anti-obesity candidate. b2b inhibited triglyceride accumulation in adipocytes in vitro and significantly reduced adiposity, body weight, and lipid metabolic disturbances in diet-induced obese mice without observable toxicity. Mechanistic studies revealed that b2b directly activates nicotinamide phosphoribosyltransferase (NAMPT) and elevates intracellular NAD⁺ levels to enhance the NAD⁺-dependent regulatory protein SIRT1 activity. This activation leads to transcriptional repression of acyl-CoA synthetase long-chain family member 1 (ACSL1), thereby inhibiting LCFAs incorporation into triglycerides. These findings demonstrate that pharmacological activation of the NAMPT-NAD⁺-SIRT1 axis by b2b offers a novel strategy for obesity treatment.
Discovery of novel tumor-targeting peptide-oncolytic peptide based conjugates (PPCs): A new paradigm for targeted oncolytic-immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(7): 4491-4523.

Oncolytic peptides, which possess synergistic oncolytic-immunotherapy effects, have exhibited advantages including unique anticancer mechanism, overcoming drug resistance and broad anticancer spectrum in clinic. Nevertheless, conventional oncolytic peptides often suffer from poor stability, limited efficacy, and moderate anticancer selectivity. In this study, the stability-, potency-, and selectivity-guided optimizations were conducted on the first-in-class oncolytic peptide Clip-71. The robust synthetic strategy, in vitro and in vivo anticancer activity, and anticancer mechanism especially immune activation ability were systematically investigated for obtained peptides. The first round of stability-guided optimization identified the mirror-image peptides represented by QY-8, which possessed strikingly high stability, as well as outstanding in vitro and in vivo anticancer activities. Subsequently, to address the limited selectivity and nonspecific distribution of oncolytic peptides, the second round of selectivity-guided and PPCs-strategy based optimization was conducted on QY-8. Strikingly, the novel PPC QY-13, which was obtained through conjugation of the SSTR2-targeting peptide Tyr³-octreotate to QY-8, exhibited most potent anticancer activities both in vitro and in vivo, enhanced immunostimulatory activity, and superior biosafety as well as tumor targeting potency. Collectively, this study not only established promising strategies to significantly improve the anticancer potential of cytotoxic peptides, but also provided the new paradigm for targeted oncolytic-immunotherapy.
High-throughput ligand discovery in living cells using the cellular protein stability enhancement assay

Acta Pharmaceutica Sinica B. 2026, 16(7): 4524-4538.

Target-based drug screening typically relies on biochemical or affinity-based assays to identify compounds that modulate or bind to purified target proteins in vitro. However, additional cellular validation is essential to confirm genuine drug-target engagements. Integrating screening and validation within a single cellular assay could greatly expedite the drug discovery process. Herein, we developed a cellular ligand discovery method called CPSEA (cellular protein stability enhancement assay), which leverages the biophysical principle of ligand-induced stabilization of target proteins containing destabilizing mutations. Using CPSEA, we identified arteannuin B and colchicine as novel ligands for FKBP12 and KRASG₁₂S, respectively. Importantly, we introduced both experimental and computational strategies to identify destabilizing mutations, thereby broadening the applicability of CPSEA for target proteins with and without known stabilizing ligands. Overall, CPSEA represents a powerful cell-based screening strategy with significant potential in target-based drug discovery.
Ultrasensitive bioorthogonal probes for selective discrimination of trace H₂S₂/H₂Sn in sulfide-competitive contexts

Xidan Tong, Xiaowei Xu, Jiaxuan Chen, Jinkang Feng, Yixing Li, Yangfei Shi, Zhen Li, Weiwei Guo, Yueqin Zheng

Acta Pharmaceutica Sinica B. 2026, 16(7): 4539-4551.

Hydrogen persulfide/polysulfides (H₂S₂/H₂Sn), as an oxidized derivative of hydrogen sulfide (H₂S), is capable of directly inducing the S-persulfidation of cysteine residues, thereby modulating the activity of relevant enzymes. Owing to its unique reactive properties, H₂S₂/H₂Sn is emerging as a central focus in the study of reactive sulfur species. Therefore, the precise detection of H₂S₂/H₂Sn in vivo is critical for elucidating their roles in redox signaling and cellular regulation. However, conventional probes face challenges such as poor sensitivity, cross-reactivity, and instability. Here, we report a bioorthogonal ether linkage fluorescent probe toolkit (Cyne-1-5) with a cyclooctyne warhead, enabling ultra-sensitive (LOD = 3.3 nmol/L), selective, and real-time tracking of H₂S₂/H₂Sn in living systems. These probes feature rapid activation (>1018-fold fluorescence activation in 5 min), broad spectral coverage (blue to NIR), and exceptional enzymatic stability. Using this toolkit, we uncovered the spontaneous oxidation of H₂S to trace H₂S₂/H₂Sn and demonstrated steric hindrance-driven self-disproportionation of persulfides, where less bulky persulfides efficiently yield H₂S₂/H₂Sn. Furthermore, we achieved the cellular-level visualization of protein S-persulfidation dynamics. This work advances persulfide chemical biology and offers transformative tools for probing H₂S₂/H₂Sn in disease mechanisms and therapeutic development.
AI-powered therapeutic aptamer drug discovery: Targeting the CT-domain of CTGF for duchenne muscular dystrophy

Acta Pharmaceutica Sinica B. 2026, 16(7): 4552-4574.

Duchenne muscular dystrophy (DMD), a fatal X-linked disorder, features progressive muscle fibrosis as a key driver of mortality. While CTGF represents a therapeutic target for DMD, its VWC-domain-targeting antibody (FG-3019) failed in clinical trials. Through experimental validation, we identified CT-domain as a superior target domain, as it contributed more fibrosis activity of CTGF than VWC-domain without elevating compensatory TGF-β1 level. Aptamers are synthetic oligonucleotides identified through SELEX, which can specifically bind to flexible protein domains through their unique 3D conformations. Their small molecular size enables effective tissue penetration while maintaining high target specificity, making them ideal CT-domain inhibitors. Nevertheless, conventional SELEX involves time-consuming and inefficient multiple screening rounds. Here, we employed our generative AI model, AptGEN, to rapidly discover a potent CT-domain specific aptamer within 42 days. This chemically modified aptamer (Apc003OA) distributed and remained in muscle tissues for an extended period, whereas FG-3019 could not. Importantly, it demonstrated better fibrosis inhibitory activity in vitro and in mdx mice when compared to FG-3019. Furthermore, Apc003OA demonstrated a favorable safety profile in mdx mice. Within 10 months, we progressed from target domain discovery, aptamer drug discovery, and then obtained both Orphan Drug Designation and Pediatric Rare Disease Designation by US Food and Drug Administration.
Targeting bacterial phosphotransferase system to prevent the dissemination of antibiotic resistance genes

Acta Pharmaceutica Sinica B. 2026, 16(7): 4575-4591.

Antimicrobial resistance (AMR) poses a significant challenge to public health and human security, with plasmid-mediated horizontal gene transfer (HGT) being a primary driver for its dissemination. Here, we identify indole analogs containing electron-withdrawing groups as a new category of HGT inhibitors. Using indole-3-acetic acid (IAA) as a representative scaffold, we demonstrate that IAA targets glycolytic enolase to deplete phosphoenolpyruvate (PEP) in donor bacteria; this suppresses phosphotransferase system (PTS) activity, blocks PtsI phosphorylation, reduces cAMP synthesis and prevents catabolite repressor protein (CRP) activation, ultimately limiting intracellular ATP availability. Concurrently, IAA attenuates reactive oxygen species (ROS) generation by inhibiting FADH₂ oxidation and riboflavin biosynthesis. The concerted reduction in ATP and ROS arrests conjugative plasmid transfer. Overall, our work suggests the potential of indole analogs as a new class of conjugative transfer inhibitors and highlights that bacterial phosphotransferase system represents a promising target to prevent the propagation of AMR.
Photobiomodulation-reprogrammed extracellular vesicles delivered via a biodegradable microneedle patch promote cardiac repair by enhancing glycolytic metabolism

Acta Pharmaceutica Sinica B. 2026, 16(7): 4592-4615.

Stem cell-derived extracellular vehicles (EVs) hold great therapeutic potential for myocardial infarction (MI). However, the efficient production of EVs with high bioactivity remains a critical bottleneck limiting their clinical translation. Here, we demonstrate that conditioned photobiomodulation (PBM) with green light is capable of activating human embryonic stem cells (hESCs) to secrete more EVs with superior cardioprotective activity. These PBM-reprogrammed hESC-EVs improve cardiac recovery in a murine MI model by promoting cardiomyocyte proliferation and angiogenesis while inhibiting apoptosis. Notably, we validate that these EVs similarly enhance the survival and proliferation of human cardiomyocytes, underscoring their translational potential. Further analysis reveals that this benefit is due to the higher miR-423-3p content in reprogrammed hESC-EVs, which enhances glycolytic metabolism and restores mitochondrial function by regulating the ZBTB7A/PKM2 axis. Moreover, we synthesize a methacryloyl hydrogel microneedle patch with superior biocompatibility, biodegradability, and mechanical strength for loading hESC-EVs, and convey the patch to the infarcted heart via a modified delivery apparatus. This system ensures the precise and sustained delivery of EVs to ischemic myocardium, offering a potent treatment for MI. Collectively, this optical and biomaterials-based approach efficiently prepares EVs with higher cardioprotective activity, providing new therapeutic strategies for heart disease.
Engineering an immuno-nanoprodrug: Photo-controlled pyroptosis synergizing with acid-activatable immunometabolic blockade for potent cancer immunotherapy

Acta Pharmaceutica Sinica B. 2026, 16(7): 4616-4633.

Although immunotherapy has revolutionized cancer treatment, antitumor immunological responses remain limited by insufficient tumor immunogenicity and immunosuppressive tumor microenvironment. Herein, pyroptosis induction is integrated into a photosensitizer to potentiate tumor immunogenicity. In this part, artesunate is disclosed to increase GSDME and modified to synthesize its ROS-cleavable prodrug, which is then installed into the self-assembled photosensitizer, resulting in a novel oil-in-water nanoplatform (BDP-pATS). The cytotoxicity, pyroptosis feature and potentiated GSDME induced by BDP-pATS are well confirmed. Subsequently, a novel acid-activatable adenosine-A2AR inhibitor is synthesized and further installed into the aforementioned platform to obtain BDP-pATS-aA2Ai, manipulating immunometabolic strategy to counterbalance the enhanced adenosine caused by pyroptosis. Such a photo-controlled and acid-activatable nanoprodrug enhances cytotoxic T cell functions while restrains regulatory T cell activities, leading to potent effects toward primary and abscopal tumor inhibition. In addition, BDP-pATS-aA2Ai also manifests desirable performance on pulmonary metastasis and tumor recurrence mouse model. To the best of our knowledge, this study presents the first concept of blocking adenosine-A2AR pathway during pyroptosis occurrence. Collectively, this work strategically combines immunometabolic interception, pyroptosis induction, photodynamic therapy and epigenetic regulation, emphasizing the significance of comprehensive therapy, which should open up a new viewpoint for cancer immunotherapy.

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