NSC 240898 was previously identified as a botulinum neurotoxin A light chain (BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.
NSC 240898 was previously identified as a botulinum neurotoxin A light chain (n class="Chemical">BoNT/A LC) endopeptidase inhibitor by screening the National Cancer Institute Open Repository diversity set. Two types of analogues have been synthesized and shown to inhibit BoNT/A LC in a FRET-based enzyme assay, with confirmation in an HPLC-based assay. These two series of compounds have also been evaluated for inhibition of anthrax lethal factor (LF), an unrelated metalloprotease, to examine enzyme specificity of the BoNT/A LC inhibition. The most potent inhibitor against BoNT/A LC in these two series is compound 12 (IC(50) = 2.5 microM, FRET assay), which is 4.4-fold more potent than the lead structure and 11.2-fold more selective for BoNT/A LC versus the anthrax LF metalloproteinase. Structure-activity relationship studies have revealed structural features important to potency and enzyme specificity.
Authors: S S Arnon; R Schechter; T V Inglesby; D A Henderson; J G Bartlett; M S Ascher; E Eitzen; A D Fine; J Hauer; M Layton; S Lillibridge; M T Osterholm; T O'Toole; G Parker; T M Perl; P K Russell; D L Swerdlow; K Tonat Journal: JAMA Date: 2001-02-28 Impact factor: 56.272
Authors: Patrick G Foran; Nadiem Mohammed; Godfrey O Lisk; Sharuna Nagwaney; Gary W Lawrence; Eric Johnson; Leonard Smith; K Roger Aoki; J Oliver Dolly Journal: J Biol Chem Date: 2002-10-14 Impact factor: 5.157
Authors: A Nowakowski; C Wang; D B Powers; P Amersdorfer; T J Smith; V A Montgomery; R Sheridan; R Blake; L A Smith; J D Marks Journal: Proc Natl Acad Sci U S A Date: 2002-08-12 Impact factor: 11.205
Authors: Rekha G Panchal; Ann R Hermone; Tam Luong Nguyen; Thiang Yian Wong; Robert Schwarzenbacher; James Schmidt; Douglas Lane; Connor McGrath; Benjamin E Turk; James Burnett; M Javad Aman; Stephen Little; Edward A Sausville; Daniel W Zaharevitz; Lewis C Cantley; Robert C Liddington; Rick Gussio; Sina Bavari Journal: Nat Struct Mol Biol Date: 2003-12-29 Impact factor: 15.369
Authors: Katerina Capková; Mark S Hixon; Sabine Pellett; Joseph T Barbieri; Eric A Johnson; Kim D Janda Journal: Bioorg Med Chem Lett Date: 2009-10-31 Impact factor: 2.823
Authors: Son T Nguyen; John D Williams; Michelle M Butler; Xiaoyuan Ding; Debra M Mills; Tommy F Tashjian; Rekha G Panchal; Susan K Weir; Chaeho Moon; Hwa-Ok Kim; Jeremiah A Marsden; Norton P Peet; Terry L Bowlin Journal: Bioorg Med Chem Lett Date: 2014-06-12 Impact factor: 2.823
Authors: Bing Li; Steven C Cardinale; Michelle M Butler; Ramdas Pai; Jonathan E Nuss; Norton P Peet; Sina Bavari; Terry L Bowlin Journal: Bioorg Med Chem Date: 2011-10-26 Impact factor: 3.641
Authors: Igor Opsenica; Vuk Filipovic; Jon E Nuss; Laura M Gomba; Dejan Opsenica; James C Burnett; Rick Gussio; Bogdan A Solaja; Sina Bavari Journal: Eur J Med Chem Date: 2012-03-30 Impact factor: 6.514
Authors: John D Williams; Son T Nguyen; Shen Gu; Xiaoyuan Ding; Michelle M Butler; Tommy F Tashjian; Timothy J Opperman; Rekha G Panchal; Sina Bavari; Norton P Peet; Donald T Moir; Terry L Bowlin Journal: Bioorg Med Chem Date: 2013-10-25 Impact factor: 3.641