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BACE1 inhibitory activity of fungal endophytic extracts from Malaysian medicinal plants
Azzeme Harun1, Richard Muhammad Johari James, Siong Meng Lim
1Collaborative Drug Discovery Research (CDDR) Group, Faculty of Pharmacy, Universiti Teknologi MARA (UiTM) Puncak Alam Campus, 42300 Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia.
Background:
BACE1 was found to be the major β-secretase in neurons and its appearance and activity were found to be elevated in the brains of AD patients. Fungal endophytic extracts for BACE1 inhibitory activity and cytotoxicity against PC-12 (a rat pheochromocytoma with neuronal properties) and WRL68 (a non-tumorigenic human hepatic) were investigated.
Methods:
Endophytes were isolated from plants collected from Kuala Pilah, Negeri Sembilan and the National Park, Pahang and the extracts were tested for BACE1 inhibition. For investigation of biological activity, the pure endophytic cultures were cultivated for 14 days on PDA plates at 28°C and underwent semipolar extraction with ethyl acetate.
Results:
Of 212 endophytic extracts (1000 μg/ml), 29 exhibited more than 90% inhibition of BACE1 in the preliminary screening. Four extracts from isolates HAB16R13, HAB16R14, HAB16R18 and HAB8R24 identified as Cytospora rhizophorae were the most active with IC(50(BACE1)) values of less than 3.0 μg/ml. The most active extract HAB16R13 was shown to non-competitively inhibit BACE1 with K(i) value of 10.0 μg/ml. HAB16R13 was considered non-potent against PC-12 and WRL68 (IC(50(CT))) of 60.0 and 40.0 μg/ml, respectively).
Conclusions:
This first report on endophytic fungal extract with good BACE1 inhibitory activity demonstrates that more extensive study is required to uncover the potential of endophytes.
Insights
Endophytic fungal extracts show promise in inhibiting Beta-secretase 1 (BACE1), an enzyme linked to Alzheimer's disease. Further research is needed to explore the therapeutic potential of these natural compounds.
Area of Science:
- Biochemistry
- Pharmacology
- Mycology
Background:
- Beta-secretase 1 (BACE1) is a key enzyme in Alzheimer's disease pathogenesis, with elevated levels observed in affected brains.
- Fungal endophytes, microorganisms residing within plant tissues, are a potential source of novel bioactive compounds.
Purpose of the Study:
- To investigate the BACE1 inhibitory activity of fungal endophytic extracts.
- To assess the cytotoxicity of these extracts against neuronal and hepatic cell lines.
Main Methods:
- Endophytes were isolated from plants and their extracts were screened for BACE1 inhibition.
- Cytotoxicity was evaluated using PC-12 and WRL68 cell lines.
- The most active extract was further analyzed for its inhibition kinetics.
Main Results:
- Out of 212 extracts, 29 showed over 90% BACE1 inhibition.
- Four extracts from Cytospora rhizophorae isolates exhibited potent BACE1 inhibition (IC50 < 3.0 μg/ml).
- The most active extract, HAB16R13, non-competitively inhibited BACE1 (Ki = 10.0 μg/ml) and displayed low cytotoxicity.
Conclusions:
- Endophytic fungal extracts, particularly from Cytospora rhizophorae, demonstrate significant BACE1 inhibitory activity.
- These findings highlight the potential of endophytes as a source for Alzheimer's disease therapeutics.
- Further investigation is warranted to explore the full therapeutic potential of these fungal endophytes.
