Delving into the Latest Updates on Aloxistatin with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Aoxistatin, AB-007, ALP-496

+ [2]

Target

CTSB x cysteine protease

Action

inhibitors

Mechanism

CTSB inhibitors(Cathepsin B inhibitors), cysteine protease inhibitors(Cysteine proteases inhibitors)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesRespiratory Diseases+ [3]

Active Indication

Anti-Glomerular Basement Membrane DiseaseAlzheimer DiseaseRNA Virus Infections

Inactive Indication-

Originator Organization

Sunnybrook Health Sciences Centre

Active Organization

Sunnybrook Health Sciences Centre

Tianjin Medical University General Hospital

American Life Science Pharmaceutical, Inc.

+ [1]

Inactive Organization-

License Organization-

Drug Highest PhasePreclinical

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC17H30N2O5

InChIKeySRVFFFJZQVENJC-IHRRRGAJSA-N

CAS Registry88321-09-9

Cathepsins are lysosomal proteases with well‐documented roles in the progression of various cancers. Among them, cathepsin B (CTSB), a cysteine protease, is notably involved in the development of breast cancer and neuroblastoma. This article, explores the potential of darifenacin as a repurposed therapeutic targeting CTSB, using molecular docking and simulation studies which demonstrate a significantly lower binding energy against CTSB (−456.268 kJ mol−1) compared to its known inhibitor, aloxistatin (−36.601 kJ mol−1). The cytotoxic efficacy of darifenacin is evaluated on IMR‐32 (neuroblastoma) and MCF‐7 (breast cancer) cells, yielding half‐maximal inhibitory concentrations (IC50) of 38.14 and 39.96 μM, respectively. Darifenacin effectively inhibits CTSB enzymatic activity by ≈1.82‐fold and ≈1.75‐fold in IMR‐32 and MCF‐7 cells, respectively, triggering intracellular reactive oxygen species generation, mitochondrial membrane potential depolarization, and cell cycle arrest. These events culminates in apoptosis‐mediated cell death, with apoptotic populations reaching 51.39% in IMR‐32 and 40.6% in MCF‐7 cells, respectively. Additionally, darifenacin disrupts lipid droplet accumulation, cellular migration, and colony‐ and sphere‐forming abilities in both cell lines. Overall, this article identifies darifenacin as a promising therapeutic agent against CTSB‐driven cancer progression.

03 Jul 2025·Nature

Substrate recognition and cleavage mechanism of the monkeypox virus core protease

Article

Author: Jia, Handi ; Liu, Hong ; Wu, Botao ; Xu, Jin ; Mao, Shengjiang ; Hu, Wanlong ; Zhang, Leike ; Hu, Shulei ; Wang, Haofeng ; Yang, Kailin ; Wang, Wei ; Nguyen, Henry C ; Cui, Wen ; Jia, Menghan ; Zhang, Yumin ; Yin, Yue ; Dong, Xuxue ; Yang, Bei ; Xie, Xiong ; Zhang, Xiaoyu ; Xiao, Gengfu ; Zhou, Hao ; Rao, Zihe ; Yang, Xiuna ; Sun, Zhanqi ; Liu, Xiaoce ; Duan, Yinkai ; Dai, Wenhao ; Gao, Yan ; Li, Dongxu ; Xiang, Yingchun ; Yang, Haitao ; Shang, Weijuan ; Cao, Junyuan ; Zhang, Mingjing ; You, Tian ; Lan, Weiqi ; Ji, Xiaoyun

Poxviruses cause severe diseases, including smallpox and mpox, that pose major threats to human health. The poxvirus core protease (Core^Pro) is essential for viral maturation and is highly conserved in poxviruses, making it an attractive antiviral target¹. However, the structure of Core^Pro remains unknown, hampering antiviral development. Here we determined the apo structure of monkeypox virus (MPXV) Core^Pro and the structure of Core^Pro in a complex with the inhibitor aloxistatin, a drug candidate for muscular dystrophy². These structures show that Core^Pro forms a homodimer that features a unique 'dancing couple' fold. The catalytic intermediate state of Core^Pro was characterized by an aldehyde derivative from a natural substrate (I-G18). This derivative binds covalently to the catalytic Cys328, shifting the active site of the viral protease from a closed conformation in the apo form to a favourable open conformation upon substrate binding. On the basis of the Core^Pro-I-G18 complex, we designed a series of peptidomimetic inhibitors with a nitrile warhead, which could covalently anchor with the catalytic Cys328. These compounds inhibit Core^Pro with half-maximal inhibitory concentrations of 44.9-100.3 nM, and exhibit potent and broad anti-poxvirus activity. Our studies provide a basis for designing wide-spectrum inhibitors against poxvirus infections.

01 Jul 2025·PHYTOMEDICINE

Gluconic acid alleviates hypertrophic scar formation through binding PLOD1, reducing p-AKT signaling and activating autophagy

Article

Author: Chen, Ling ; Zhang, Enyuan ; Sun, Yue ; Zou, Jijun ; Li, Jun ; Zeng, Siqi ; Li, Jingyun ; Yan, Qiyue

BACKGROUND:

Hypertrophic scarring represents a major clinical challenge worldwide, with current treatment strategies showing limited effectiveness. Gluconic acid (GLA), a naturally occurring glucose metabolite found in fruits, honey, kombucha tea, and wine, may provide new approach for scar treatment.

PURPOSE:

This study aimed to investigate the anti-scarring properties of GLA and underlying molecular mechanisms.

STUDY DESIGN:

A comprehensive experimental study combined in vitro hypertrophic scar fibroblasts and in vivo rabbit ear scar model assays.

METHODS:

Hypertrophic scar fibroblasts were treated with GLA. Cell counting kit-8 (CCK-8) and flow cytometry were used to evaluate cell viability and apoptosis. The collagen and ACTA2 (actin alpha 2, smooth muscle) expressions were analyzed by qPCR and western blot. A rabbit ear scar model was applied to assess GLA's effects on scar formation and collagen deposition. Transcriptome sequencing, pull-down assays, western blotting and rescue experiments using AKT agonist SC79 were employed to identify GLA-regulated pathways. Molecular docking, pull-down, cellular thermal shift assays and co-localization studies were used to assess GLA's interaction with PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1). E64d, MG132 and QX77 were added to analyze GLA's function mechanisms on PLOD1 protein expression. Autophagy activation was evaluated through autophagic flux assay, transmission electron microscopy and autophagy related protein expression analysis. Mitochondrial membrane potential was detected by JC-1 staining.

RESULTS:

GLA suppresses collagen and ACTA2 expressions and exerted a mild inhibitory effect on cell proliferation or apoptosis in hypertrophic scar fibroblasts. And it diminishes scar formation and collagen content in the rabbit ear scar model. AKT (protein kinase B) and phosphorylated AKT (p-AKT) levels were significantly reduced after GLA treatment. Rescue experiments confirmed that GLA's effects are mediated through the AKT pathway. Moreover, GLA interacts with PLOD1, resulting in its autophagy-lysosomal degradation. Additionally, GLA treatment activated autophagy, reduced mTOR protein expressions, and had no significant effect on mitochondrial membrane depolarization, further contributing to its anti-scarring effects.

CONCLUSION:

Our findings demonstrate that GLA attenuates hypertrophic scarring through multi-modal mechanisms involving PLOD1 targeting, AKT/mTOR pathway inhibition, and autophagy activation. This study provides both mechanistic insights and therapeutic potential for GLA in scar treatment.

100 Deals associated with Aloxistatin

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External Link

KEGG	Wiki	ATC	Drug Bank
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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Anti-Glomerular Basement Membrane Disease	Preclinical	China	Tianjin Medical University General Hospital	10 Mar 2024
Alzheimer Disease	Preclinical	United States	American Life Science Pharmaceutical, Inc.	01 Jul 2013
RNA Virus Infections	Discovery	Germany	Deutsches Elektronen-Synchrotron DESY	17 Apr 2024