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The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-β peptides.

Lei X, Yu J, Niu Q, Liu J, Fraering PC, Wu F - Sci Rep (2015)

Bottom Line: Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient.Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC.A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.

ABSTRACT
Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus

Structural requirements of dihydroergocristine for suppressing the activity of γ-secretase.(a) Effect of 200 μM dihydroergocristine (DHEC) analogs on C100-Flag cleavage by purified γ-secretase. The blots were processed under the same experiment conditions and each blot contained negative (DMSO) and positive (0.5 μM DAPT) controls as well as 200 μM DHEC. For full-length blots, please see Supplementary Fig. S10. (b) Dose-dependent effects of 2-bromo-α-ergocryptine and CABA on C100-Flag processing by purified γ-secretase. (c) Structure-activity relationship of DHEC analogs for inhibiting γ-secretase. The relative levels of AICD-Flag were estimated by densitometry and the quantification data are shown in Supplementary Fig. S6.
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f3: Structural requirements of dihydroergocristine for suppressing the activity of γ-secretase.(a) Effect of 200 μM dihydroergocristine (DHEC) analogs on C100-Flag cleavage by purified γ-secretase. The blots were processed under the same experiment conditions and each blot contained negative (DMSO) and positive (0.5 μM DAPT) controls as well as 200 μM DHEC. For full-length blots, please see Supplementary Fig. S10. (b) Dose-dependent effects of 2-bromo-α-ergocryptine and CABA on C100-Flag processing by purified γ-secretase. (c) Structure-activity relationship of DHEC analogs for inhibiting γ-secretase. The relative levels of AICD-Flag were estimated by densitometry and the quantification data are shown in Supplementary Fig. S6.

Mentions: To identify the minimal core structure of DHEC that is responsible for suppressing the activity of γ-secretase, we next tested commercially available structural analogs of DHEC in our assay with purified γ-secretase (Table 1 and Fig. 3a). α-Ergocryptine is the closest analog of α-dihydroergocryptine, a component of ergoloid mesylates, while β-dihydroergocryptine is the other component of ergoloid mesylates14, both of which have similar chemical structures to DHEC (Table 1). Both 200 μM α–ergocryptine and 200 μM β-dihydroergocryptine inhibited the activity of γ-secretase (Fig. 3a; Supplementary Fig. S6a). DHEC, α-ergocryptine and β-dihydroergocryptine all contain a dimethyl group at the R2 position (corresponding to the side chain of valine in all three molecules) and a hydrophobic group at the R1 position (corresponding to the side chains phenylalanine, isoleucine and leucine, respectively; Table 1). In contrast, close analogs of DHEC, i.e., ergotamine and dihydroergotamine (DHE), both of which contain a methyl group at the R2 position instead of the dimethyl group in DHEC, did not inhibit γ-secretase activity (Table 1, Fig. 3a and Supplementary Fig. S6a).


The FDA-approved natural product dihydroergocristine reduces the production of the Alzheimer's disease amyloid-β peptides.

Lei X, Yu J, Niu Q, Liu J, Fraering PC, Wu F - Sci Rep (2015)

Structural requirements of dihydroergocristine for suppressing the activity of γ-secretase.(a) Effect of 200 μM dihydroergocristine (DHEC) analogs on C100-Flag cleavage by purified γ-secretase. The blots were processed under the same experiment conditions and each blot contained negative (DMSO) and positive (0.5 μM DAPT) controls as well as 200 μM DHEC. For full-length blots, please see Supplementary Fig. S10. (b) Dose-dependent effects of 2-bromo-α-ergocryptine and CABA on C100-Flag processing by purified γ-secretase. (c) Structure-activity relationship of DHEC analogs for inhibiting γ-secretase. The relative levels of AICD-Flag were estimated by densitometry and the quantification data are shown in Supplementary Fig. S6.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4644980&req=5

f3: Structural requirements of dihydroergocristine for suppressing the activity of γ-secretase.(a) Effect of 200 μM dihydroergocristine (DHEC) analogs on C100-Flag cleavage by purified γ-secretase. The blots were processed under the same experiment conditions and each blot contained negative (DMSO) and positive (0.5 μM DAPT) controls as well as 200 μM DHEC. For full-length blots, please see Supplementary Fig. S10. (b) Dose-dependent effects of 2-bromo-α-ergocryptine and CABA on C100-Flag processing by purified γ-secretase. (c) Structure-activity relationship of DHEC analogs for inhibiting γ-secretase. The relative levels of AICD-Flag were estimated by densitometry and the quantification data are shown in Supplementary Fig. S6.
Mentions: To identify the minimal core structure of DHEC that is responsible for suppressing the activity of γ-secretase, we next tested commercially available structural analogs of DHEC in our assay with purified γ-secretase (Table 1 and Fig. 3a). α-Ergocryptine is the closest analog of α-dihydroergocryptine, a component of ergoloid mesylates, while β-dihydroergocryptine is the other component of ergoloid mesylates14, both of which have similar chemical structures to DHEC (Table 1). Both 200 μM α–ergocryptine and 200 μM β-dihydroergocryptine inhibited the activity of γ-secretase (Fig. 3a; Supplementary Fig. S6a). DHEC, α-ergocryptine and β-dihydroergocryptine all contain a dimethyl group at the R2 position (corresponding to the side chain of valine in all three molecules) and a hydrophobic group at the R1 position (corresponding to the side chains phenylalanine, isoleucine and leucine, respectively; Table 1). In contrast, close analogs of DHEC, i.e., ergotamine and dihydroergotamine (DHE), both of which contain a methyl group at the R2 position instead of the dimethyl group in DHEC, did not inhibit γ-secretase activity (Table 1, Fig. 3a and Supplementary Fig. S6a).

Bottom Line: Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient.Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC.A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai, China.

ABSTRACT
Known γ-secretase inhibitors or modulators display an undesirable pharmacokinetic profile and toxicity and have therefore not been successful in clinical trials for Alzheimer's disease (AD). So far, no compounds from natural products have been identified as direct inhibitors of γ-secretase. To search for bioactive molecules that can reduce the amount of amyloid-beta peptides (Aβ) and that have better pharmacokinetics and an improved safety profile, we completed a screen of ~400 natural products by using cell-based and cell-free γ-secretase activity assays. We identified dihydroergocristine (DHEC), a component of an FDA- (Food and Drug Administration)-approved drug, to be a direct inhibitor of γ-secretase. Micromolar concentrations of DHEC substantially reduced Aβ levels in different cell types, including a cell line derived from an AD patient. Structure-activity relationship studies implied that the key moiety for inhibiting γ-secretase is the cyclized tripeptide moiety of DHEC. A Surface Plasmon Resonance assay showed that DHEC binds directly to γ-secretase and Nicastrin, with equilibrium dissociation constants (Kd) of 25.7 nM and 9.8 μM, respectively. This study offers DHEC not only as a new chemical moiety for selectively modulating the activity of γ-secretase but also a candidate for drug repositioning in Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus