Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4-dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease. Our studies have shown that modifications of this compound are tolerated and result in improved inhibitors, with the best compound having an IC(50) of 0.23 μM. Given the inconsistency of structure-activity relationship trends observed across similar compounds, this data argues for caution in extrapolating across structural series.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352981 | PMC |
| http://dx.doi.org/10.1016/j.bmcl.2012.04.019 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Analysis of Microbial Siderophores by Mass Spectrometry.
Methods Mol Biol
April 2020
Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic.
Siderophores represent important microbial virulence factors and infection biomarkers. Their monitoring in fermentation broths, bodily fluids, and tissues should be reproducible. Similar isolation, characterization, and quantitation studies can often have conflicting results, and without proper documentation of sample collection, data processing, and analysis methods, it is difficult to reexamine the data and reconcile these differences.
View Article and Find Full Text PDFConformational analysis of a secondary hydroxamic acid in aqueous solution by NOE spectroscopy.
Magn Reson Chem
February 2013
Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA.
Hydroxamic acids are metal-binding compounds used by micro-organisms and possess applications in medicine and industry. Hydroxamic acids favor two conformations, E and Z; metal binding is limited to the Z conformation. The Z conformation may be identifiable by NOE spectroscopy, but analysis is complicated by the potential for long-range coupling as well as for relayed NOEs due to conformational switching.
View Article and Find Full Text PDFReexamining hydroxamate inhibitors of botulinum neurotoxin serotype A: extending towards the β-exosite.
Bioorg Med Chem Lett
June 2012
Fox Chase Chemical Diversity Center, Doylestown, PA 18902, USA.
Botulinum neurotoxins (BoNTs) are the most toxic proteins known to man, exposure to which results in flaccid paralysis. Given their extreme potency, these proteins have become studied as possible weapons of bioterrorism; however, effective treatments that function after intoxication have not progressed to the clinic. Here, we have reexamined one of the most effective inhibitors, 2,4-dichlorocinnamyl hydroxamate, in the context of the known plasticity of the BoNT/A light chain metalloprotease.
View Article and Find Full Text PDFPentacopper(II) 12-metallacrown-4 complexes with alpha- and beta-aminohydroxamic acids in aqueous solution: a reinvestigation.
J Inorg Biochem
January 2003
Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Università di Parma, Parco Area delle Scienze 17A, I-43100 Parma, Italy.
A reinvestigation of the equilibria of (S)-alpha-alaninehydroxamic acid (alpha-Alaha) and (R)-aspartic-beta-hydroxamic acid (Asp-beta-ha) with copper(II) was performed in aqueous solution in order to clarify some contradictory literature reports regarding the stoichiometry of the polynuclear complexes formed. beta-Alaninehydroxamic acid (beta-Alaha, HL), for which the formation of a planar 12-metallacrown-4, [Cu(5)L(4)H(-4)](2+), was already reported, was also re-examined for comparison. Among the different techniques used (potentiometry, absorption spectrophotometry, spectropolarimetry and electrospray ionization mass spectrometry), ES data allowed to define unambiguously that all these three ligands form the same pentanuclear species.
View Article and Find Full Text PDFHemosiderosis in rodents and the effect of acetohydroxamic acid on urinary iron excretion.
Exp Hematol
November 1986
Previously reported animal models of hemosiderosis fall short of simulating the human disease state of transfusion-induced hemosiderosis. An explanation for this was found by reexamining heat-treated red blood cell (rbc) loading in the mouse. After 18 intraperitoneal transfusions, each equal to two-thirds of mouse rbc volume, liver Fe reaches a level of 0.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!