Chemical QuantArray: A Quantitative Tool for Mass Spectrometry Imaging

Stopka, Sylwia A.; Ruiz, Daniela; Baquer, Gerard; Bodineau, Clément; Hossain, Md Amin; Pellens, Valentina T.; Regan, Michael S.; Pourquié, Olivier; Haigis, Marcia C.; Bi, Wenya L.; Coy, Shannon M.; Santagata, Sandro; Agar, Nathalie Y. R.; Basu, Sankha S.

doi:10.1021/acs.analchem.3c00803

Cited by 6 publications

(6 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Pharmacodynamic profiling was carried out using hemizygous mice expressing human SOD1 G93A (“fast-line” Jackson Laboratory; B6SJL-Tg(SOD1*G93A)1Gur/J, also known as SOD1-G93A stock- 002726) [ 13 ]. Mice were bred to express YFP in neurons in anticipation of BBB-penetration assays and Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging (MALDI MSI) analysis according to the published protocol [ 68 , 69 ]. Extraction of SOD1 G93A from red blood cell (RBC) protein was performed as previously described [ 48 ].…”

Section: Methodsmentioning

confidence: 99%

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Hossain,

Sarin,

Donnelly

et al. 2024

PLoS Biol

Self Cite

View full text Add to dashboard Cite

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS) cases. A shared effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers that seed toxic aggregates. Considerable research effort has been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but unfortunately, this has not yet resulted in a treatment. We hypothesized that cyclic thiosulfinate cross-linkers, which selectively target a rare, 2 cysteine-containing motif, can stabilize fALS-causing SOD1 variants in vivo. We created a library of chemically diverse cyclic thiosulfinates and determined structure-cross-linking-activity relationships. A pre-lead compound, “S-XL6,” was selected based upon its cross-linking rate and drug-like properties. Co-crystallographic structure clearly establishes the binding of S-XL6 at Cys 111 bridging the monomers and stabilizing the SOD1 dimer. Biophysical studies reveal that the degree of stabilization afforded by S-XL6 (up to 24°C) is unprecedented for fALS, and to our knowledge, for any protein target of any kinetic stabilizer. Gene silencing and protein degrading therapeutic approaches require careful dose titration to balance the benefit of diminished fALS SOD1 expression with the toxic loss-of-enzymatic function. We show that S-XL6 does not share this liability because it rescues the activity of fALS SOD1 variants. No pharmacological agent has been proven to bind to SOD1 in vivo. Here, using a fALS mouse model, we demonstrate oral bioavailability; rapid engagement of SOD1G93A by S-XL6 that increases SOD1G93A’s in vivo half-life; and that S-XL6 crosses the blood–brain barrier. S-XL6 demonstrated a degree of selectivity by avoiding off-target binding to plasma proteins. Taken together, our results indicate that cyclic thiosulfinate-mediated SOD1 stabilization should receive further attention as a potential therapeutic approach for fALS.

show abstract

Section: Methodsmentioning

confidence: 99%

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Hossain,

Sarin,

Donnelly

et al. 2024

PLoS Biol

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mimetics for MALDI quantitation were performed using a tissue microarray (TMA) mold. 31 15N-glutamate (332143, Sigma-Aldrich) was resuspended and pipetted into rat tail collagen I in microcentrifuge tubes. 15N-glutamate concentrations ranging from 0 – 30 mM were pipetted into 1.5 mm core diameter channels of the 40% gelatin TMA mold.…”

Section: Methodsmentioning

confidence: 99%

“…Tissue specimens were homogenized and diluted 10-fold using LC-MS grade water before extraction using acetonitrile (1:1 [v/v], 0.2 µM of chlorpropamide as an internal standard with acetonitrile) according to previously published methods. 31,32 Both perampanel and levetiracetam were quantified using a 5500 ESI triple-quadruple mass spectrometer (Sciex, Framingham, MA) coupled with an Acquity ultra pressure liquid chromatograph (UPLC) (Waters Corp., Milford, MA) as previously described. 33,34 The instrument was operated in positive-ion mode and 5 μL of each sample was injected on an Acquity HSS T3, 1.8 μM, 2.1 mm × 150 mm UPLC column (Milford, MA) at 50 °C.…”

Section: Drug Quantitation By Lc-msmentioning

confidence: 99%

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma

Tobochnik,

Regan,

Dorotan

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Background Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the AMPA-R antagonist, perampanel, on intraoperative electrophysiologic hyperexcitability and clinical outcomes. Methods An open-label trial was performed comparing perampanel to standard of care (SOC) in patients undergoing resection of newly-diagnosed radiologic high-grade glioma. Perampanel was administered as a pre-operative loading dose followed by maintenance therapy until progressive disease or up to 12-months. SOC treatment involved levetiracetam for 7-days or as clinically indicated. The primary outcome of hyperexcitability was defined by intra-operative electrocorticography high frequency oscillation (HFO) rates. Seizure-freedom and overall survival (OS) were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and metabolites were measured by mass spectrometry. Results HFO rates were similar between perampanel-treated and SOC cohorts. The trial was terminated early after interim analysis for futility, and outcomes assessed in 11 patients (7 perampanel-treated, 4 SOC). Over a median 281 days of post-enrollment follow-up, 27% of patients had seizures, including 14% treated with perampanel and 50% treated with SOC. OS in perampanel-treated patients was similar to a glioblastoma reference cohort (p=0.81). Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Conclusions A peri-operative loading regimen of perampanel was safe and well-tolerated, with similar peritumoral hyperexcitability as in levetiracetam-treated patients. Maintenance anti-glutamatergic therapy was not observed to impact survival outcomes.

show abstract

“…4C-D). To quantify the levels of these compounds, we developed a tissue microarray mimetic 27 containing carboplatin and Gadavist in which the compounds were diluted and spiked into a tissue homogenate to generate standard calibration curves (SI Fig. 11).…”

Section: Quantification Of Carboplatin and Gadavist In Focused Ultras...mentioning

confidence: 99%

Spatial Profiling of Metals through Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging

Stopka,

Bodineau,

Baquer

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

The spatial-omic analysis of biomolecules such as nucleic acids, lipids, metabolites, and proteins is advancing the study of biological systems and processes in a physio-pathological context. Here, we describe an innovative matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) method to detect metals within biological tissues using instrumentation that is widely available in research and clinical laboratories. We characterize the spatial distribution of metals in diverse settings including mouse embryogenesis, genetic disorders leading to abnormal metal accumulation, and preclinical testing for improved platinum-based chemotherapy delivery through focused ultrasound across the blood-brain barrier. Spatial metal profiling will advance research studies and the clinical analysis of metal-related diseases, enabling more precise use of metal-based therapies and advances in diverse scientific fields beyond biomedicine.

show abstract

Chemical QuantArray: A Quantitative Tool for Mass Spectrometry Imaging

Cited by 6 publications

References 37 publications

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Evaluating protein cross-linking as a therapeutic strategy to stabilize SOD1 variants in a mouse model of familial ALS

Pilot trial of perampanel on peritumoral hyperexcitability and clinical outcomes in newly diagnosed high-grade glioma

Spatial Profiling of Metals through Matrix-Assisted Laser Desorption Ionization Mass Spectrometry Imaging

Contact Info

Product

Resources

About