A β-Secretase (BACE1) Inhibitor Hispidin from the Mycelial Cultures of Phellinus linteus

Abstract

In the course of screening for anti-dementia agents from natural products, a β-secretase (BACE1) inhibitor was isolated from the culture broth of Phellinus linteus and identified as hispidin. It showed an IC₅₀ value of 4.9 × 10^-6 M and a Ki value of 8.4 × 10^-6 M. The compound was a non-competitive inhibitor. Hispidin also inhibited a prolyl endopeptidase (IC₅₀ = 1.6 × 10^-5 M, Ki = 2.4 × 10^-5 M), but it was less inhibitory to α-secretase (TACE) and other serine proteases such as chymotrypsin, trypsin, and elastase.

Key words

Phellinus linteus - Hymenochaetaceae - mycelial culture - phenylpropanoid - hispidin - β-secretase inhibitor - Alzheimer

References

• 1 Sisodia S S, Price D L. Role of the β-amyloid protein in Alzheimer’s disease.  FASEB J. 1995;  9 366-70
• 2 Glenner G G, Wong C W. Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.  Biochem Biophys Res Commun. 1984;  120 885-90
• 3 Selkoe D J. Alzheimer’s disease: genes, proteins, and therapy.  Physiol Rev. 2001;  81 741-66
• 4 Vassar R. β-Secretase (BACE) as a drug target for Alzheimer’s disease.  Adv Drug Deliv Rev. 2002;  54 1589-602
• 5 Dewachter I, Van Leuven F. Secretases as targets for the treatment of Alzheimer’s disease: the prospects.  Lancet Neurol. 2002;  1 409-16
• 6 Wilson C A, Doms R W, Zheng H, Lee V M. Presenilins are not required for Aβ 42 production in the early secretory pathway.  Nature Neurosci. 2002;  5 849-55
• 7 Anderson J P, Barbour R, Basi G S, Caccavello R, Davis D, Doan M. et al . Purification and cloning of amyloid precursor protein β-secretase from human brain.  Nature. 1999;  402 533-7
• 8 Vassar R, Bennett B D, Babu-Khan S, Khan S, Mendiaz A, Denis P. et al . β-Secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE1.  Science. 1999;  286 735-41
• 9 Schmidt B. Aspartic protease involved in Alzheimer’s disease.  ChemBioChem. 2003;  4 366-78
• 10 Ghosh A K, Shin D, Downs B, Koelsch G, Lin X, Ermolieff J J. et al . Design of potent inhibitors for human brain memapsin 2 (β-secretase).  J Am Chem Soc. 2000;  122 3522-3
• 11 Bakker A V, Jung S, Spencer R W, Vinick F J, Faraci W S. Slow-tight binding of prolyl endopeptidase by benzyloxycarbonylprolinal.  Biochem J. 1990;  274 559-62
• 12 Toda S, Obi Y, Kimura K, Hamagishi Y, Tomita K, Komiyana N. et al . Eurystatins A and B, new prolyl endopeptidase inhibitors. I. Taxonomy, production, isolation and biological activities. J.  Antibiotics. 1992;  45 1573-9
• 13 Chung C H, Ines H E, Almeda S, Goldberg A L. Purification of Escherichia coli of a periplasmic protein that is potent inhibitor of pancreatic protease.  J Biol Chem. 1983;  258 11 032-8
• 14 Hubert F, Gaertner J, Antonie J, Puigserver A J. Increased activity and stability of polyethyleneglycol-modified trypsin.  Enzyme Microb Technol. 1992;  14 150-5
• 15 Bieth J, Spiess G, Camille G W. The synthesis and analytical use of a highly sensitive and convenient substrate of elastase.  Biochem Med. 1974;  11 350-7
• 16 Adam W, Saha-Moeller C R, Veit M, Markus W, Welke B. A convenient synthesis of hispidin from piperonal. Synthesis 1994: 1133-4
• 17 Klaar M, Wolfgang S. Fungus pigments, XXVII. Isolation of hispidin and 3,14′-bihispidinyl from Phellinus pomaceus (Poriales).  Chem Ber. 1997;  110 1058-62
• 18 Gonindard C, Bergonzi C, Denier C, Sergheraert C, Klaebe A, Chavant L. et al . Synthetic hispidin, a PKC inhibitor, is more cytotoxic toward cancer cells than normal cells in vitro .  Cell Biol Toxicol. 1997;  13 141-53
• 19 Buxbaum J D, Liu K -N, Luo Y, Slack J L, Stocking K L, Peschon J J. et al . Evidence that tumor necrosis factor alpha converting enzyme is involved in regulated α-secretase cleavage of the Alzheimer amyloid protein precursor.  J Biol Chem. 1998;  273 27 765-7
• 20 Katsube N, Sunaga K, Chuang D -M, Ishitani R. ONO-1603, a potential antidementia drug, shows neuroprotective effects and increases m3-muscarinic receptor mRNA levels in differentiating rat cerebellar granule neurons.  Neurosci Lett. 1996;  214 151-4
• 21 Ghosh A K, Bilcer G, Harwood C, Kawahama R, Shin D, Hussain K A. et al . Structure-based design: potent inhibitors of human brain memapsin 2 (β-secretase).  J Med Chem. 2001;  44 2865-8
• 22 Miyamoto M, Matsui J, Fukumoto H, Tarui N. Preparation of 2-[2-amino- or 2-(N-heterocyclyl)ethyl]-6-(4-biphenylylmethoxy)tetralin derivatives as β-secretase inhibitors. PCT Int Appl 2001 WO 087 293
• 23 Ramakrishna N VS, Kumar E KSV, Kulkarni A S, Jain A K, Bhat R G, Parikh S. et al . Screening of natural products for new leads as inhibitors of β-amyloid production: Latifolin from Dalbergia sissoo .  Ind J Chem. 2001;  40B 539-40
• 24 Jeon S -Y, Bae K, Seong Y -H, Song K -S. Green tea catechins as BACE1 (β-secretase) inhibitor.  Bioorg Med Chem Lett. 2003;  13 3905-8