Search results for: James J. Schmidt

Items from 1 to 16 out of 16 results

article

Targeted delivery into motor nerve terminals of inhibitors for SNARE‐cleaving proteases via liposomes coupled to an atoxic botulinum neurotoxin

Om P. Edupuganti, Saak V. Ovsepian, Jiafu Wang, Tomas H. Zurawski, more

The FEBS Journal > 279 > 14 > 2555 - 2567

A targeted drug carrier (TDC) is described for transferring functional proteins or peptides into motor nerve terminals, a pivotal locus for therapeutics to treat neuromuscular disorders. It exploits the pronounced selectivity of botulinum neurotoxin type B (BoNT/B) for interacting with acceptors on these cholinergic nerve endings and becoming internalized. The gene encoding an innocuous BoNT/B protease‐inactive...

article

Rapid product analysis and increased sensitivity for quantitative determinations of botulinum neurotoxin proteolytic activity

Benjamin Rowe, James J. Schmidt, Leonard A. Smith, S. Ashraf Ahmed

Analytical Biochemistry > 2010 > 396 > 2 > 188-193

The ultimate molecular action of botulinum neurotoxin (BoNT) is a Zn-dependent endoproteolytic activity on one of the three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. There are seven serotypes (A–G) of BoNT having distinct cleavage sites on the SNARE substrates. The proteolytic activity is located on the N-terminal light chain (Lc) domain and is used extensively...

article

A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate

Jorge E. Zuniga, James J. Schmidt, Timothy Fenn, James C. Burnett, more

Structure > 2008 > 16 > 10 > 1588-1597

Botulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (K _i = 41 nM) that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to...

article

A Refined Pharmacophore Identifies Potent 4-Amino-7-chloroquinoline-Based Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease

James C. Burnett, Dejan Opsenica, Kamaraj Sriraghavan, Rekha G. Panchal, more

Journal of Medicinal Chemistry > 2007 > 50 > 9 > 2127 - 2136

article

Bis-imidazoles as molecular probes for peripheral sites of the zinc endopeptidase of botulinum neurotoxin serotype A

Isidro Merino, Jason D. Thompson, Charles B. Millard, James J. Schmidt, more

Bioorganic & Medicinal Chemistry > 2006 > 14 > 10 > 3583-3591

Botulinum neurotoxin serotype A (BoNTA) is highly toxic, and its antidote is currently unavailable. The essential light-chain subunit of BoNTA is a zinc endopeptidase that can be used as a target for developing antidotes. However, the development of high-affinity, small-molecule inhibitors of the endopeptidase is as challenging as the development of small-molecule inhibitors of protein–protein complexation...

article

Serotype-selective, small-molecule inhibitors of the zinc endopeptidase of botulinum neurotoxin serotype A

Jewn Giew Park, Peter C. Sill, Edward F. Makiyi, Alfonso T. Garcia-Sosa, more

Bioorganic & Medicinal Chemistry > 2006 > 14 > 2 > 395-408

Botulinum neurotoxin serotype A (BoNTA) is one of the most toxic substances known. Currently, there is no antidote to BoNTA. Small molecules identified from high-throughput screening reportedly inhibit the endopeptidase—the zinc-bound, catalytic domain of BoNTA—at a drug concentration of 20μM. However, optimization of these inhibitors is hampered by challenges including the computational evaluation...

article

Botulinum Neurotoxin Serotype F: Identification of Substrate Recognition Requirements and Development of Inhibitors with Low Nanomolar Affinity

James J. Schmidt, Robert G. Stafford

Biochemistry > 2005 > 44 > 10 > 4067 - 4073

article

Conformational sampling of the botulinum neurotoxin serotype a light chain: implications for inhibitor binding

James C. Burnett, James J. Schmidt, Connor F. McGrath, Tam L. Nguyen, more

Bioorganic & Medicinal Chemistry > 2005 > 13 > 2 > 333-341

Botulinum neurotoxins (BoNTs) are the most potent of the known biological toxins, and consequently are listed as category A biowarfare agents. Currently, the only treatments against BoNTs include preventative antitoxins and long-term supportive care. Consequently, there is an urgent need for therapeutics to counter these enzymes––post exposure. In a previous study, we identified a number of small,...

article

Novel small molecule inhibitors of botulinum neurotoxin A metalloprotease activity

James C. Burnett, James J. Schmidt, Robert G. Stafford, Rekha G. Panchal, more

Biochemical and Biophysical Research Communications > 2003 > 310 > 1 > 84-93

Botulinum neurotoxins (BoNTs) are among the most lethal biological substances to have been weaponized and are listed as biodefense category A agents. Currently, no small molecule (non-peptidic) therapeutics exist to counter this threat; hence, identifying and developing compounds that inhibit BoNTs is a high priority. In the present study, a high-throughput assay was used to identify small molecules...

article

A high-affinity competitive inhibitor of type A botulinum neurotoxin protease activity

James J. Schmidt, Robert G. Stafford

FEBS Letters > 2002 > 532 > 3 > 423-426

The peptide N-acetyl-CRATKML-amide is an effective inhibitor of type A botulinum neurotoxin (BoNT A) protease activity [Schmidt et al., FEBS Lett. 435 (1998) 61-64]. To improve inhibitor binding, the peptide was modified by replacing cysteine with other sulfhydryl-containing compounds. Ten peptides were synthesized. One peptide adapted the structure of captopril to the binding requirements of BoNT...

article

High-Throughput Assays for Botulinum Neurotoxin Proteolytic Activity: Serotypes A, B, D, and F

James J. Schmidt, Robert G. Stafford, Charles B. Millard

Analytical Biochemistry > 2001 > 296 > 1 > 130-137

Botulinum neurotoxins (BoNT) are zinc metalloproteases that cleave and inactivate cellular proteins essential for neurotransmitter release. Because the paralytic effect of BoNT is a consequence of its enzymatic activity, selective inhibitors may be useful as drugs or as tools for further research. To expedite inhibitor discovery, we developed high-throughput, solid-phase protease activity assays for...

article

Cloning, Expression, and One-Step Purification of the Minimal Essential Domain of the Light Chain of Botulinum Neurotoxin Type A

Saloumeh Kadkhodayan, Mark S. Knapp, James J. Schmidt, Sarah E. Fabes, more

Protein Expression and Purification > 2000 > 19 > 1 > 125-130

A truncated but functional form of the botulinum neurotoxin A light chain (Tyr 9–Leu 415) has been cloned into the three bacterial expression vectors, pET 28, pET 30, and PGEX-2T, and produced as fusion proteins. This 406-amino-acid light chain was expressed with 1 six-histidine tag (LC-pET28), 2 six histidine tags and a S-tag (LC-pET30), or a six-histidine tag and a glutathione S-transferase tag...

article

Type A botulinum neurotoxin proteolytic activity: development of competitive inhibitors and implications for substrate specificity at the S ₁ ' binding subsite

James J. Schmidt, Robert G. Stafford, Karen A. Bostian

FEBS Letters > 1998 > 435 > 1 > 61-64

Type A botulinum neurotoxin (botox A) is a zinc metalloprotease that cleaves only one peptide bond in the synaptosomal protein, SNAP-25. Single-residue changes in a 17-residue substrate peptide were used to develop the first specific, competitive inhibitors of its proteolytic activity. Substrate analog peptides with P ₄ , P ₃ , P ₂ ' or P ₃ ' cysteine were readily hydrolyzed...

article

Toxins isolated from the venom of the Brazilian coral snake (Micrurus frontalis frontalis) include hemorrhagic type phospholipases A ₂ and postsynaptic neurotoxins

Brian R. Francis, Nelson Jorge Da Silva, Corrine Seebart, Luciana Lyra Casais E Silva, more

Toxicon > 1997 > 35 > 8 > 1193-1203

Two sets of proteins have been purified from the venom of the Brazilian coral snake, Micrurus frontalis frontalis. One set has mol. wts, as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), in the 8000-13,000 range and includes some proteins which are toxic to mice and others which are not. These proteins appear to be isoforms of postsynaptic toxins. The other set shows...

article

Endoproteinase Activity of Type A Botulinum Neurotoxin: Substrate Requirements and Activation by Serum Albumin

James J. Schmidt, Karen A. Bostian

The Protein Journal > 1997 > 16 > 1 > 19-26

Type A botulinum neurotoxin, a zinc-dependent endoproteinase that selectively cleaves the neuronal protein SNAP-25, can also cleave relatively short peptides. We found that bovine and other serum albumins stimulated the type A-catalyzed hydrolysis of synthetic peptide substrates, through a direct effect on the kinetic constants of the reaction. Furthermore, with bovine serum albumin in the assays,...

article

Structure-function studies of waglerin I, a lethal peptide from the venom of wagler's pit viper, Trimeresurus wagleri

James J. Schmidt, Scott A. Weinstein

Toxicon > 1995 > 33 > 8 > 1043-1049

Waglerins are 22-24 residue lethal peptides, found in the venom of Trimeresurus (Tropidolaemus) wagleri. The effects upon lethality and immunoreactivity resulting from structural modifications of these peptides were studied. A synthetic analogue with alanine residues in place of the two half-cystines of native peptide was nontoxic, suggesting that the single intramolecular disulfide bond in waglerins...

Filter options

Publication date

Set your own date range

Content availability

Available (14)
None (2)

Keywords

Data set

Elsevier (12)
ACS (2)
Springer (1)
Wiley (1)

Journal

Bioorganic & Medicinal Chemistry (3)
Analytical Biochemistry (2)
FEBS Letters (2)
Toxicon (2)
Biochemical and Biophysical Research Communications (1)
Biochemistry (1)
Journal of Medicinal Chemistry (1)
Protein Expression and Purification (1)
Structure (1)
The FEBS Journal (1)
The Protein Journal (1)
more

INFONA - science communication portal

Search results for: James J. Schmidt

Add recipient

Sending message cancelled

Are you sure you want to cancel sending this message?

Send message

Filter options

Publication date

Date range setting

Set the date range to filter the displayed results. You can set a starting date, ending date or both. You can enter the dates manually or choose them from the calendar.

Content availability

Keywords

Data set

Journal

Reporting an error / abuse

Sending the report failed

Accessibility options