作者: Raju, Rajesh ; Nadh, Anuroopa G ; Adithya, Krishna S B ; Kunhikrishnan, M Jitha ; Rehman, Niyas ; Ramakrishnan, Krishnapriya ; Revikumar, Amjesh ; Sudhakaran, P R ; Ravi, Vishal

Alzheimer's Disease is a chronic progressive neurodegenerative disorder characterized by impaired intellect and cognitive functions. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) by initiating the amyloid cascade. Despite significant clinical efforts, most BACE1 inhibitors have failed to yield potent pharmacological effects. Our previous study, identified a group of natural compounds with satisfying pharmacological profiles with high affinity to BACE1, out of which the compound, 'convolidine' emerged as the most promising candidate based on the in-silico parameters such as docking score, interacting residues, binding energy, drug-likeness, ADMET, and biological activity prediction. The present study focused on the inhibitory potential of convolidine against BACE1 using dynamics simulation followed by protein-protein docking and in-vitro validation. Molecular dynamics simulation demonstrated that the BACE1-convolidine complex remained stable throughout the entire 200 ns simulation period. Also, the results of the post-dynamic docking study showed a reduced substrate affinity of BACE1 to its substrate, APP (Amyloid precursor protein), when BACE1 is bound to convolidine, suggesting compounds inhibitory potential. This in-silico assessment was validated in-vitro using a FRET-based BACE1 activity assay, where the result well aligned with the computational predictions. The findings revealed that convolidine could effectively inhibit BACE1, with an IC50 value of 0.49 µM, providing a solid foundation for its development as a promising therapeutic agent for AD management.

2025-10-01·BRAIN RESEARCH BULLETIN

BACE1 as an early biomarker and its relevance to risk factors for Alzheimer’s disease

Review

作者: Ohno, Masuo

While the β-secretase BACE1 is responsible for the rate-limiting initial step to generate amyloid-β (Aβ) peptides, BACE1 inhibitor clinical trials have been halted due to a lack of efficacy and/or safety concerns at symptomatic/prodromal stages of Alzheimer's disease (AD). These trials were often targeted at high levels of BACE1 inhibition (>70 %) and ended up with signs of mild cognitive worsening instead of expected improvement. BACE1 concentration and activity are elevated in the cerebrospinal fluid and plasma/serum as well as brains of patients with mild cognitive impairment and AD dementia. Interestingly, recent evidence suggests that these fluid-based biomarkers reflective of BACE1 elevation may be associated with yet asymptomatic pathological changes in preclinical AD populations who are at high-risk for developing AD. Consistent with these findings, it has been demonstrated that exposures to major environmental and genetic risks such as diabetes, sleep disturbances, seizure, vascular disorders, stress, apolipoprotein E4, etc. converge on BACE1 elevation in humans and animal models, which may contribute to triggering sporadic AD. Moreover, vicious cycles exist between BACE1/Aβ elevations and certain prognostic conditions, further accelerating disease progression. Conversely, protective factors for AD are associated with reduced BACE1 level/activity. This review provides an overview of BACE1 alterations as common responses to a broad battery of AD risk and protective factors. The findings validate BACE1 as a biomarker for preclinical AD status that may be useful for earlier diagnosis and identifying subpopulations of individuals under AD risks who would benefit from preventive low-dose BACE1 inhibitor treatment with a higher probability.

2025-08-07·FITOTERAPIA

Potent BACE1 inhibitory and neuroprotective activities of three lignans, styraxlignolide A, masutakeside I, and egonol, isolated from Styrax japonica.

Article

作者: Kim, Hoon ; Kwon, Yoon-Ju ; Shin, Woong-Hee ; Kim, Eonmi ; Oh, Jong Min

Intracellular amyloid-β (Aβ) accumulation causes Alzheimer's disease (AD), and thus Aβ-related inhibitors, especially inhibitors of β-secretase 1, known as β-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) have been developed to treat AD. The purpose is to evaluate BACE1 inhibitory activity of the compounds isolated from Styrax japonica stem bark, traditionally used as herbal medicines. In this study, seven compounds were isolated, including three lignans, styraxlignolide A, masutakeside I, and egonol. Styraxlignolide A showed potent inhibitory activity against BACE1 with an IC₅₀ value of 0.173 μM, followed by masutakeside I and egonol (IC₅₀ = 0.376 and 1.509 μM, respectively), with mixed-type inhibition and low toxicity to normal MDCK and neuroblastoma SH-SY5Y cells. Furthermore, egonol, aglycone of masutakeside I, had neuroprotective activity in SH-SY5Y cells and Aβ₄₂ aggregation inhibitory activity with blood-brain barrier permeability. The binding energies of styraxlignolide A, masutakeside I, and egonol, for BACE1 were predicted to be -11.753, -11.041, and - 8.413 kcal/mol, respectively. It was found that styraxlignolide A was the most potent BACE1 inhibitor compared with other herbal molecules reported to date. In conclusion, styraxlignolide A, masutakeside I, and egonol are potent mixed-type BACE1 inhibitors, suggesting that they can be used as drug candidates for therapeutic agents of AD.

项与 BIVP-1 相关的新闻（医药）

2015-07-27

·BioSpace

Embattled Vitae Pharma and Boehringer Ingelheim Relationship Takes Another Blow, Drops BACE Inhibitor Program for Alzheimer’s

July 27, 2015 By Mark Terry , BioSpace.com Breaking News Staff Fort Washington, Penn.-based Vitae Pharmaceuticals, Inc. , announced today that Boehringer Ingelheim had informed Vitae that it was terminating the two companies’ collaboration and license agreement for orally-active beta secretase (BACE) inhibitors to treat Alzheimer’s disease and other indications. On Feb. 26, 2015, the company announced that Boehringer Ingelheim had voluntarily placed BI-1181181 , a BACE inhibitor, on temporary clinical hold. The drug was underoing a Phase I clinical trial for the treatment and prevention of Alzheimer’s. The trial was halted to investigate skin reactions that some study participants showed during the trial. “Our partner is working diligently to evaluate and understand this observation,” said Richard Gregg , chief scientific officer of Vitae in a statement in February. “We are confident that the analysis will result in a clear understanding of how to proceed with BI-1181181, and we remain committed to our partner and the BACE program. Depending on the outcome of the evaluation and Boehringer Ingelheim’s decision, we expect that either BI-1181181 or its structurally distinct, Phase I-ready back up will be advanced, with the goal of delivering a medicine with disease-modifying benefits to patients suffering from Alzheimer’s disease.” Vitae has not indicated specifics as to why Boehringer Ingelheim has terminated the agreement. Prior to this announcement, the company expedited Boehringer to start a Phase II trial for BI-1147560 and VTP-36951 by the end of the year. In pre-clinical testing, the two compounds were shown to be safe and well-tolerated and could lower amyloid beta levels in the brain by more than 90 percent. “We are grateful for BI’s support for the BACE program, as we have demonstrated significant progress toward the development of an oral BACE inhibitor for Alzheimer’s disease,” said Jeff Hatfield , president and chief executive officer of Vitae in a statement. “With the termination of this agreement, Vitae expects to receive the rights to the BACE program, most notably BI-1147560 / VTP-36951 , and to work with BI to effect an orderly transfer. We plan to assess the program to determine the appropriate next steps.” Vitae and Boehringer Ingelheim are having a tough year working together. In June, Vitae announced that its drug, VTP-34072 , a potential add-on therapy for diabetes with Metformin that it co-developed with Boehringer Ingelheim , failed to significantly cut blood sugar levels of patients. Analysts aren’t very hopeful for the drug. The companies intend to test VTP-34072 alone, as a monotherapy, but Liana Moussatos , an analyst with Wedbush indicated she didn’t expect much unless the trial had “spectacular results.” “ Incyte did a trial on the same target,” said Thomas Shrader , an analyst with Stifel . “The data looked pretty good, but they stopped the program. A chemistry company will always be at the mercy of the targets it uses.” has been all over the place the past year. Shares traded for $5.75 on Oct. 13, 2014, rose to a high of $21.97 on Dec. 18, 2014, dropped to $11.99 on Jan. 22, 2015, and rose again to $17.34 on Jan. 27, 2015. Shares dropped again on Mar. 9, 2015 to $10.66, rose to a recent high of $16.50 on June 23, 2015 and currently is priced at $9.73 per share. The company has been given a consensus recommendation of “Buy” from six brokerages. Piper Jaffray analysts maintained an “overweight” rating with a price target of $20.50, down from $23 in a note on Thursday, July 2. Wedbush analysts reiterated a “Buy” rating and a price target of $20, down from $21 on June 29. JMP Securities analysts downgraded from “Outperform” to “Market Perform” on June 29. On June 8, Zacks upgraded from “Sell” to “Hold.”

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