Johann Conradt Bremer. In Vino Veritas – 230 Jahre Weinhandelstradition in Göttingen

Catch and Anchor Approach To Combat Both Toxicity and Longevity of Botulinum Toxin A

“…As discussed by Bremer et al, this inhibitor design strategy could increase the effective molarity of an electrophilic moiety for Cys165, in turn enhancing k inact . 39 Although initial attempts to design a bifunctional inhibitor with a benzoquinone electrophile and an amino acetamide ZBG were mostly unsuccessful, the importance of overcoming BoNT/A LC persistence dictates a deeper investigation into this design strategy. BoNT/A LC endopeptidase activity is dependent on zinc-mediated hydrolysis of SNAP-25 between residues Gln197 and Arg198.…”

“…51 The most successful inhibitor design for BoNT/A LC, both in vitro and in vivo, has targeted this zinc-binding region and is headlined by hydroxamates, quinolinols, and recently, steroidal 4-aminoquinolines. [24][25][26][27][28][29][30][31][32][33][52][53][54][55][56] Despite their well-known liabilities, hydroxamates remain the most potent BoNT/A LC inhibitors. As such, the hydroxamate functional group was selected for our bifunctional inhibitor design.…”

“…Finally, deprotection of the THP protecting group afforded the 3 rd generation bifunctional compounds (53)(54)(55)(56).…”

“…35 As a follow up to the previous report, a library of electrophilic fragments was screened and benzoquinone was identified as an active warhead for irreversible inhibition of BoNT/A LC. 39 Efforts to elaborate upon the benzoquinone pharmacophore (5), including an attempt to deliver the first bifunctional (zinc-chelating and covalent) inhibitor, significantly compromised covalent inhibition. The selenium-containing compound Ebselen (6), initially investigated in 2010 by Saunders et al and more recently by the Bogyo group, was shown to irreversibly inhibit BoNT/A by reaction with Cys165, with a reported k inact /K i of 23,000 M −1 s −1 .…”

5. Phylogenetic reconstruction based on morphology

“…The Bremer support (or branch support value) is frequently used in morphology-based studies, and also in molecular investigations (Bremer 1994). It is 1 for a tree with no homoplasy at all and would be 0.75 if 50% of the characters have a CI of 0.5 (CI of 1 in the other 50%), or 0.5 if all characters have a CI of 0.5.…”