Identification of a potent botulinum neurotoxin a protease inhibitor using in situ lead identification chemistry

被引：96

作者：

Boldt, GE

Kennedy, JP

Janda, KD

机构：

[1] Scripps Res Inst, Skaggs Inst Chem Biol, Dept Chem, La Jolla, CA 92037 USA

[2] Scripps Res Inst, Skaggs Inst Chem Biol, Dept Immunol, La Jolla, CA 92037 USA

[3] Scripps Res Inst, WIRM, La Jolla, CA 92037 USA

来源：

ORGANIC LETTERS | 2006年 / 8卷 / 08期

关键词：

D O I：

10.1021/ol0603211

中图分类号：

O62 [有机化学];

学科分类号：

070303 ; 081704 ;

摘要：

Botulinum neurotoxins (BoNTs), etiological agents of the deadly food poisoning disease botulism, are the most toxic proteins currently known. By using in situ lead identification chemistry, we have uncovered the first class of inhibitors that displays nanomolar potency. From a 15 mu M lead compound, structure-activity relationship studies were performed granting the most potent BoNT/A inhibitor reported to date that displays an inhibition constant of 300 nM.

引用

页码：1729 / 1732

页数：4

共 23 条

[1] Genetic and immunological comparison of anti-botulinum type A antibodies from immune and non-immune human phage libraries [J].

Amersdorfer, P ;

Wong, C ;

Smith, T ;

Chen, S ;

Deshpande, S ;

Sheridan, R ;

Marks, JD .

VACCINE, 2002, 20 (11-12) :1640-1648

[2] Botulinum toxin as a biological weapon - Medical and public health management [J].

Arnon, SS ;

Schechter, R ;

Inglesby, TV ;

Henderson, DA ;

Bartlett, JG ;

Ascher, MS ;

Eitzen, E ;

Fine, AD ;

Hauer, J ;

Layton, M ;

Lillibridge, S ;

Osterholm, MT ;

O'Toole, T ;

Parker, G ;

Perl, TM ;

Russell, PK ;

Swerdlow, DL ;

Tonat, K .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2001, 285 (08) :1059-1070

[3] Solid-phase synthesis of hydroxamic acid based TNF-α convertase inhibitors [J].

Barlaam, B ;

Koza, P ;

Berriot, J .

TETRAHEDRON, 1999, 55 (23) :7221-7232

[4] A novel linkage for the solid-phase synthesis of hydroxamic acids [J].

Bauer, U ;

Ho, WB ;

Koskinen, AMP .

TETRAHEDRON LETTERS, 1997, 38 (41) :7233-7236

[5]

BOLDT GE, 2006, IN PRESS J COMB CHEM

[6] Conformational sampling of the botulinum neurotoxin serotype a light chain: implications for inhibitor binding [J].

Burnett, JC ;

Schmidt, JJ ;

McGrath, CF ;

Nguyen, TL ;

Hermone, AR ;

Panchal, RG ;

Vennerstrom, JL ;

Kodukula, K ;

Zaharevitz, DW ;

Gussio, R ;

Bavari, S .

BIOORGANIC & MEDICINAL CHEMISTRY, 2005, 13 (02) :333-341

[7] Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity [J].

Burnett, JC ;

Schmidt, JJ ;

Stafford, RG ;

Panchal, RG ;

Nguyen, TL ;

Hermone, AR ;

Vennerstrom, JL ;

McGrath, CF ;

Lane, DJ ;

Sausville, EA ;

Zaharevitz, DW ;

Gussio, R ;

Bavari, S .

BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2003, 310 (01) :84-93

[8]

Burns CJ, 1998, ANGEW CHEM INT EDIT, V37, P2848, DOI 10.1002/(SICI)1521-3773(19981102)37:20<2848::AID-ANIE2848>3.0.CO

[9]

2-C

[10]

Dankwardt SM, 1998, SYNLETT, P761

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