2. Academic Validation
  3. Development of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection

Development of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection

  • Biomed Pharmacother. 2025 Feb:183:117851. doi: 10.1016/j.biopha.2025.117851.
Suddhasatwa Banerjee 1,  Ying-Ting Hsu 2,  Duc-Hieu Nguyen 3,  Shiu-Hwa Yeh 4,  Ke-Chi Liou 1,  Jr-Jiun Liu 3,  Jing-Ping Liou 5,  Jian-Ying Chuang 6
Affiliations

Affiliations

  • 1 School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
  • 2 Ph.D. Program in Medical Neuroscience, Taipei Medical University and National Health Research Institutes, Taipei 11031, Taiwan; Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan.
  • 3 Ph.D. Program in Medical Neuroscience, Taipei Medical University and National Health Research Institutes, Taipei 11031, Taiwan.
  • 4 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli County 35053, Taiwan.
  • 5 School of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan; Ph.D. Program in Drug Discovery and Development Industry, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan. Electronic address: jpl@tmu.edu.tw.
  • 6 Ph.D. Program in Medical Neuroscience, Taipei Medical University and National Health Research Institutes, Taipei 11031, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan; International Master Program in Medical Neuroscience, Taipei Medical University, New Taipei City 23564, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei 11031, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80780, Taiwan. Electronic address: chuangcy@tmu.edu.tw.
PMID: 39837213 DOI: 10.1016/j.biopha.2025.117851
Abstract

Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet. Revelations from single-cell RNA Sequencing (scRNA-seq) performed to determine cell-type heterogeneity and gene expression changes in brain tissue indicated that brain trauma increases the expression of lysine-specific demethylase 1 (LSD1) and secretase 2 (BACE2). To capitalize on this finding, a medicinal chemistry campaign was conducted to pragmatically insert tranylcypromine, an LSD1 inhibitor, into a carefully designed BACE2 inhibitory template (BACE2-IN-1). Additionally, tranylcypromine was structurally modified to enhance the effects of LSD1 inhibition in TBI. As a result, a tractable neuroprotective agent, BACE2-IN-1/tranylcypromine-based compound 4, was identified, showing potential to maintain Neuro-2a cell survival by alleviating mitochondrial damage after oxidative stress. Compound 4 also restored TBI-mediated inhibition of the Cholesterol biosynthetic pathway (mevalonate pathway) and damage of redox metabolism, increasing neuroprotective effects. Furthermore, behavioral assays, including nest-building and cognitive performance tests, demonstrated significant improvement in mice post-TBI following treatment with compound 4. Taken together, the outcomes of this study validate the favorable effects of inhibiting LSD1 and Beta-secretase in mitigating mitochondrial stress and promoting neurometabolic recovery in TBI. These findings pave the way for the development of rationally designed inhibitors as promising neuroprotective agents, potentially addressing unmet clinical needs in TBI treatment.

Keywords

Beta-secretase; LSD1; Oxidative stress; Sterol biosynthesis; Tranylcypromine; Traumatic brain injury.

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