Reduce drug uptake in the development of resistance DOI
Raquel Alves, Joana Jorge, Maria Inês Costa

et al.

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 53 - 75

Published: Nov. 1, 2024

Language: Английский

Predicting substrates for orphan Solute Carrier Proteins using multi-omics datasets DOI Open Access
Yimo Zhang, Simon Newstead, Peter Sarkies

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 24, 2024

Abstract Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR loss-of-function screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.

Language: Английский

Citations

0
Evidence for the Role of the Mitochondrial ABC Transporter MDL1 in the Uptake of Clozapine and Related Molecules into the Yeast Saccharomyces cerevisiae DOI Creative Commons
Chrispian W. Theron, J. Enrique Salcedo-Sora, Justine M. Grixti

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(7), P. 938 - 938

Published: July 13, 2024

Clozapine is an antipsychotic drug whose accumulation in white cells can sometimes prove toxic; understanding the transporters and alleles responsible thus highly desirable. We used a strategy which yeast (Saccharomyces cerevisiae) CRISPR-Cas9 knock-out library was exposed to cytotoxic concentrations of clozapine determine those absence made it more resistant; we also recognised structural similarity fluorescent dye safranin O (also known as T) clozapine, allowing be surrogate marker. Strains lacking mitochondrial ABC transporter MDL1 (encoded by YLR188W) showed substantial resistance clozapine. overexpression conferred extra sensitivity admitted massive increase cellular uptake O, determined using flow cytometry microscopically. Yeast mitochondria no such unusual accumulation. Mitochondrial main means S. cerevisiae. The closest human homologue cerevisiae ABCB10.

Language: Английский

Citations

0
Stichoposide C and Rhizochalin as Potential Aquaglyceroporin Modulators DOI Creative Commons
Ji Woo Im, Ju Hyun Lim, Valentin A. Stonik

et al.

Marine Drugs, Journal Year: 2024, Volume and Issue: 22(8), P. 335 - 335

Published: July 25, 2024

Aquaporins (AQPs) are a family of integral membrane proteins that selectively transport water and glycerol across the cell membrane. Because AQPs involved in wide range physiological functions pathophysiological conditions, AQP-based therapeutics may have broad potential for clinical utility, including disorders energy balance. However, AQP modulators not yet been developed as suitable candidates applications. In this study, to identify AQPs, we screened 31 natural products by measuring permeability mouse erythrocyte membranes using stopped-flow light scattering method. None tested compounds substantially affected osmotic permeability. several considerably Stichoposide C increased membranes, whereas rhizochalin decreased it at nanomolar concentrations. Immunohistochemistry revealed AQP7 was main aquaglyceroporin membranes. We further verified effects stichoposide on aquaglyceroporins human AQP3-expressing keratinocyte cells. C, but D, AQP3-mediated transepithelial transport, peracetyl aglycon most potent inhibitor among derivatives. Collectively, might function AQP3 AQP7, suggests possibility these drug modulators.

Language: Английский

Citations

0
Predicting substrates for orphan Solute Carrier Proteins using multi- omics datasets DOI Creative Commons
Ying Zhang, Simon Newstead, Peter Sarkies

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 5, 2024

Abstract Solute carriers (SLC) are integral membrane proteins responsible for transporting a wide variety of metabolites, signaling molecules and drugs across cellular membranes. Despite key roles in metabolism, pharmacology, around one third SLC ‘orphans’ whose substrates unknown. Experimental determination is technically challenging given the range possible physiological candidates. Here, we develop predictive algorithm to identify correlations between expression levels intracellular metabolite concentrations by leveraging existing cancer multi-omics datasets. Our predictions recovered known SLC-substrate pairs with high sensitivity specificity compared simulated random pairs. CRISPR loss-of-function screen data metabolic pathway adjacency further improved performance our algorithm. In parallel, combined drug profiles predict new SLC-drug interactions. Together, provide novel bioinformatic pipeline substrate SLCs, offering opportunities de-orphanise SLCs important implications understanding their health disease.

Language: Английский

Citations

0
Reduce drug uptake in the development of resistance DOI
Raquel Alves, Joana Jorge, Maria Inês Costa

et al.

Elsevier eBooks, Journal Year: 2024, Volume and Issue: unknown, P. 53 - 75

Published: Nov. 1, 2024

Language: Английский

Citations

0