Upload
others
View
2
Download
0
Embed Size (px)
Citation preview
微生物創薬について
北里大学北里生命科学研究所日本学士院会員大村 智
資料6
Screening for new bioactive compounds
Liquid culture
Culture broth
Bioassay
Metabolite analysis Jar fermenter
• Purification• Structural
analysis
• Identification• Preservation
Strain
Compound
Colony
Antibacterialactivity
Enzyme activity
HPLC
StrainPure culture
R & D
Source
Retention time (min)
Staurosporine(Inhibitor of protein kinases)
S. Ōmura et al, J. Antibiot. 30, 275 (1977)T. Tamaoki et al., Biochem. Biophys. Res. Comm., 135, 397 (1986)
Saccharothrix aerocolonigenes subsp. staurosporeus AM-2282T
(Lentzea albida AM-2282)
Staurosporine: 1st natural Indolocarbazole
Complex structure of staurosporine with the catalytic sub-unit of cAMP-dependent protein kinase
H-bond
Y122
E170
V123
L173
staurosporine
E127
E121
V57
K72
D184
T183
F54F327
M120
D. Bossemeyer et al., Structure, 17, 1627 (1997)
(courtesy of Dr H. Gouda)
Gefitinib (IressaⓇ)2)Imatinib (Gleevec®)1.2)
For use:Chronic myelogenouse leukemia(慢性骨髄性白血病)
For use: Nonsmall-cell lung carcinoma
(非小細胞肺癌)
1) N. P. Shah et al., Oncogene 22, 7389 (2003)2) S. B. Bharate et al., Chem. Rev. 113, 6761 (20130
Kitasato Institute : some key discoveries
(proteosome inhibitor)
S. Ōmura et al., J. Antibiot., 44, 113, 117 (1991)G. Fenteany et al., Science, 268, 726 (1995)E. J. Corey et al., Chem. Pharm. Bull. 47, 1-10 (1999)
Omuralide
Prof. Konrad Bloch1963 Nobel Laureate
Prof. E. J. Corey1990 Nobel Laureate
For use:Multiple myeloma (多発生骨髄腫)Mantle cell Lymphoma(マントル細胞リンパ腫)
Bortezomib(Velcade®)
P. Masdehors, S. Ōmura et al., Br. J. Haematol., 105, 752 (1999)R. B. Shirtey et al., Neoplasia 7, 1104 (2005)
Streptomyces avermectinius (S. avermitilis)
The avermectin producing strain
(ー: 1mm)
Ivermectin development
Endectocide
R. Burg et al., Antimicrob. Agents Chemother.,15, 361 (1979) G. Albers-Schönberg, J. Am. Chem. Soc., 103,4216 (1981)
J. C. Chabala et al., J. Med. Chem.,23, 1134 (1980)
Structure : 16-membered macrolide Bioactivity : Nematocidal and insecticidalMode of action : Glutamate-gated chloride channel
Onchocerca volvulus (microfilaria, 290 mm)
Onchocerciasis: the helminth parasite
Simulium damnosum
Onchocerciasis : the disease vector