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All Outputs (38)

Vegetable oils composition affects the intestinal lymphatic transport and systemic bioavailability of co-administered lipophilic drug cannabidiol (2022)
Journal Article
Feng, W., Qin, C., Abdelrazig, S., Bai, Z., Raji, M., Darwish, R., …Gershkovich, P. (2022). Vegetable oils composition affects the intestinal lymphatic transport and systemic bioavailability of co-administered lipophilic drug cannabidiol. International Journal of Pharmaceutics, 624, Article 121947. https://doi.org/10.1016/j.ijpharm.2022.121947

Although natural sesame oil has been shown to facilitate the lymphatic delivery and oral bioavailability of the highly lipophilic drug cannabidiol (CBD), considerable variability remains an unresolved challenge. Vegetable oils differ substantially in... Read More about Vegetable oils composition affects the intestinal lymphatic transport and systemic bioavailability of co-administered lipophilic drug cannabidiol.

Distribution of a highly lipophilic drug cannabidiol into different lymph nodes following oral administration in lipidic vehicle (2022)
Journal Article
Jewell, A., Brookes, A., Feng, W., Ashford, M., Gellert, P., Butler, J., …Gershkovich, P. (2022). Distribution of a highly lipophilic drug cannabidiol into different lymph nodes following oral administration in lipidic vehicle. European Journal of Pharmaceutics and Biopharmaceutics, 174, 29-34. https://doi.org/10.1016/j.ejpb.2022.03.014

Efficient delivery of highly lipophilic drugs or prodrugs to the mesenteric lymph nodes (MLN) can be achieved following oral administration with lipids. However, it remains unclear which specific MLN can be targeted and to what extent. Moreover, the... Read More about Distribution of a highly lipophilic drug cannabidiol into different lymph nodes following oral administration in lipidic vehicle.

Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents (2021)
Journal Article
Shao, H., Foley, D. W., Huang, S., Abbas, A. Y., Lam, F., Gershkovich, P., …Wang, S. (2021). Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents. European Journal of Medicinal Chemistry, 214, Article 113244. https://doi.org/10.1016/j.ejmech.2021.113244

Cyclin-dependent kinases (CDKs) are a family of Ser/Thr kinases involved in cell cycle and transcriptional regulation. CDK9 regulates transcriptional elongation and this unique property has made it a potential target for several diseases. Due to the... Read More about Structure-based design of highly selective 2,4,5-trisubstituted pyrimidine CDK9 inhibitors as anti-cancer agents.

Strawberry decreases intraluminal and intestinal wall hydrolysis of testosterone undecanoate (2021)
Journal Article
Zgair, A., Dawood, Y., Ibrahem, S. M., Lee, J. B., Feng, W., Fischer, P. M., & Gershkovich, P. (2021). Strawberry decreases intraluminal and intestinal wall hydrolysis of testosterone undecanoate. Molecules, 26(1), Article 233. https://doi.org/10.3390/molecules26010233

Male hypogonadism is often treated by testosterone (T) replacement therapy such as oral administration of the ester prodrug, testosterone undecanoate (TU). However, the systemic exposure to T following oral TU is very low due to esterase-mediated met... Read More about Strawberry decreases intraluminal and intestinal wall hydrolysis of testosterone undecanoate.

Targeted delivery of lopinavir to HIV reservoirs in the mesenteric lymphatic system by lipophilic ester prodrug approach (2020)
Journal Article
Qin, C., Chu, Y., Feng, W., Fromont, C., He, S., Ali, J., …Gershkovich, P. (2021). Targeted delivery of lopinavir to HIV reservoirs in the mesenteric lymphatic system by lipophilic ester prodrug approach. Journal of Controlled Release, 329, 1077-1089. https://doi.org/10.1016/j.jconrel.2020.10.036

© 2020 Elsevier B.V. The combined antiretroviral therapy (cART) can efficiently suppress HIV replication, but the cessation of cART usually results in viral rebound, mostly due to the presence of viral reservoirs. The mesenteric lymphatic system, inc... Read More about Targeted delivery of lopinavir to HIV reservoirs in the mesenteric lymphatic system by lipophilic ester prodrug approach.

Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I (2020)
Journal Article
Stephenson, Z. A., Harvey, R. F., Pryde, K. R., Mistry, S., Hardy, R. E., Serreli, R., …Willis, A. E. (2020). Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I. eLife, 9, Article e55845. https://doi.org/10.7554/elife.55845

Disruption of mitochondrial function selectively targets tumour cells that are dependent on oxidative phosphorylation. However, due to their high energy demands, cardiac cells are disproportionately targeted by mitochondrial toxins resulting in a los... Read More about Identification of a novel toxicophore in anti-cancer chemotherapeutics that targets mitochondrial respiratory complex I.

A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin (2019)
Journal Article
Lee, J. B., Radhi, M., Cipolla, E., Gandhi, R. D., Sarmad, S., Zgair, A., …Gershkovich, P. (2019). A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin. Scientific Reports, 9, Article 15760. https://doi.org/10.1038/s41598-019-52254-x

Although adenosine and its analogues have been assessed in the past as potential drug candidates due to the important role of adenosine in physiology, only little is known about their absorption following oral administration. In this work, we have st... Read More about A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin.

Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics (2019)
Journal Article
Pathak, M., Manna, R., Li, C., Kaira, B. G., Hamad, B. K., Belviso, B. D., …Emsley, J. (2019). Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics. Acta Crystallographica. Section d, Structural Biology, 75(6), 578-591. https://doi.org/10.1107/s2059798319006910

© 2019 International Union of Crystallography. Coagulation factor XII (FXII) is a key initiator of the contact pathway, which contributes to inflammatory pathways. FXII circulates as a zymogen, which when auto-activated forms factor XIIa (FXIIa). Her... Read More about Crystal structures of the recombinant β-factor XIIa protease with bound Thr-Arg and Pro-Arg substrate mimetics.

1-Hydroxy-xanthine derivatives inhibit the human Caf1 nuclease and Caf1-containing nuclease complexes via Mg2+-dependent binding (2019)
Journal Article
Airhihen, B., Pavanello, L., Jadhav, G. P., Fischer, P. M., & Winkler, G. S. (2019). 1-Hydroxy-xanthine derivatives inhibit the human Caf1 nuclease and Caf1-containing nuclease complexes via Mg2+-dependent binding. FEBS Open Bio, 9(4), 717-727. https://doi.org/10.1002/2211-5463.12605

In eukaryotic cells, cytoplasmic mRNA is characterised by a 3’ poly(A) tail. The shortening and removal of poly(A) tails (deadenylation) by the Ccr4‐Not nuclease complex leads to reduced translational efficiency and RNA degradation. Using recombinant... Read More about 1-Hydroxy-xanthine derivatives inhibit the human Caf1 nuclease and Caf1-containing nuclease complexes via Mg2+-dependent binding.

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system (2018)
Journal Article
Lee, J. B., Zgair, A., Malec, J., Kim, T. H., Kim, M. G., Ali, J., …Gershkovich, P. (2018). Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system. Journal of Controlled Release, 286, 10-19. https://doi.org/10.1016/j.jconrel.2018.07.022

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for... Read More about Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system.

Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B (2018)
Journal Article
Zyryanova, A. F., Weis, F., Faille, A., Abo Alard, A., Crespillo-Casado, A., Sekine, Y., …Ron, D. (2018). Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B. Science, 359(6383), https://doi.org/10.1126/science.aar5129

The integrated stress response (ISR) is a conserved translational and transcriptional program affecting metabolism, memory, and immunity. The ISR is mediated by stress-induced phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) tha... Read More about Binding of ISRIB reveals a regulatory site in the nucleotide exchange factor eIF2B.

Multiple linear regression modelling to predict the stability of polymer-drug solid dispersions: comparison of the effects of polymers and manufacturing methods on solid dispersion stability (2018)
Journal Article
Fridgeirsdottir, G., Harris, R., Dryden, I. L., Fischer, P. M., & Roberts, C. J. (2018). Multiple linear regression modelling to predict the stability of polymer-drug solid dispersions: comparison of the effects of polymers and manufacturing methods on solid dispersion stability. Molecular Pharmaceutics, 15(5), https://doi.org/10.1021/acs.molpharmaceut.8b00021

Solid dispersions can be a successful way to enhance the bioavailability of poorly soluble drugs. Here 60 solid dispersion formulations were produced using ten chemically diverse, neutral, poorly soluble drugs, three commonly used polymers, and two m... Read More about Multiple linear regression modelling to predict the stability of polymer-drug solid dispersions: comparison of the effects of polymers and manufacturing methods on solid dispersion stability.

Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor (2018)
Journal Article
Whittaker, S. R., Barlow, C., Martin, M. P., Mancusi, C., Wagner, S., Self, A., …Workman, P. (in press). Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor. Molecular Oncology, 12(3), https://doi.org/10.1002/1878-0261.12148

Deregulation of the cyclin-dependent kinases (CDKs) has been implicated in the pathogenesis of multiple cancer types. Consequently, CDKs have garnered intense interest as therapeutic targets for the treatment of cancer. We describe herein the molecul... Read More about Molecular profiling and combinatorial activity of CCT068127: a potent CDK2 and CDK9 inhibitor.

Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation (2017)
Journal Article
Zgair, A., Lee, J. B., Wong, J. C. M., Taha, D. A., Aram, J., Virgilio, D. D., …Gershkovich, P. (2017). Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation. Scientific Reports, 7, 1-12. https://doi.org/10.1038/s41598-017-15026-z

Cannabidiol (CBD) and ?9-tetrahydrocannabinol (THC) have well documented immunomodulatory effects in vitro, but not following oral administration in humans. Here we show that oral co-administration of cannabinoids with lipids can substantially increa... Read More about Oral administration of cannabis with lipids leads to high levels of cannabinoids in the intestinal lymphatic system and prominent immunomodulation.

Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs (2017)
Journal Article
Fischer, P. M. (in press). Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs. Journal of Medicinal Chemistry, 61(9), https://doi.org/10.1021/acs.jmedchem.7b00772

Vitamin K antagonists (VKA) have long been the default drugs for anticoagulant management in venous thrombosis. While efficacious, they are difficult to use due to interpatient dose–response variability and the risks of bleeding. The approval of fond... Read More about Design of small-molecule active-site inhibitors of the S1A family proteases as procoagulant and anticoagulant drugs.

Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation (2017)
Journal Article
Hamad, B. K., Pathak, M., Manna, R., Fischer, P. M., Emsley, J., & Dekker, L. V. (2017). Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation. Journal of Thrombosis and Haemostasis, 15(9), 1818-1828. https://doi.org/10.1111/jth.13773

Background: Corn trypsin inhibitor (CTI) has selectivity for serine proteases coagulation factor XII (FXII) and trypsin. CTI is in widespread use as a reagent that specifically inhibits the intrinsic pathway of blood coagulation but not the extrinsic... Read More about Assessment of the protein interaction between coagulation factor XII and corn trypsin inhibitor by molecular docking and biochemical validation.

Development of cordycepin formulations for preclinical and clinical studies (2017)
Journal Article
Lee, J. B., Adrower, C., Qin, C., Fischer, P. M., de Moor, C. H., & Gershkovich, P. (2017). Development of cordycepin formulations for preclinical and clinical studies. AAPS PharmSciTech, 18(8), 3219-3226. https://doi.org/10.1208/s12249-017-0795-0

There is extensive literature on in vivo studies with cordycepin but these studies were generally conducted without validation of the various formulations, especially in terms of the solubility of cordycepin in the dosing vehicles used. Cordycepin is... Read More about Development of cordycepin formulations for preclinical and clinical studies.

PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz (2017)
Journal Article
Crespillo-Casado, A., Chambers, J. E., Fischer, P. M., Marciniak, S. J., & Ron, D. (2017). PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz. eLife, 6, Article e26109. https://doi.org/10.7554/eLife.26109

Dephosphorylation of translation initiation factor 2 (eIF2α) terminates signalling in the mammalian integrated stress response (ISR) and has emerged as a promising target for modifying the course of protein misfolding diseases. The [(o-chlorobenzylid... Read More about PPP1R15A-mediated dephosphorylation of eIF2α is unaffected by Sephin1 or Guanabenz.

Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays (2017)
Journal Article
Lee, J. B., Zgair, A., Taha, D. A., Zang, X., Kagan, L., Kim, T. H., …Gershkovich, P. (2017). Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays. European Journal of Pharmaceutics and Biopharmaceutics, 114, 38-42. https://doi.org/10.1016/j.ejpb.2016.12.027

In this study, Caco-2 permeability results from different laboratories were compared. Six different sets of apparent permeability coefficient (Papp) values reported in the literature were compared to experimental Papp obtained in our laboratory. The... Read More about Quantitative analysis of lab-to-lab variability in Caco-2 permeability assays.

Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma (2016)
Journal Article
Lee, J. B., Zgair, A., Kim, T. H., Kim, M. G., Yoo, S. D., Fischer, P. M., & Gershkovich, P. (2017). Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma. Journal of Chromatography B, 1040, 73-80. https://doi.org/10.1016/j.jchromb.2016.11.024

Bexarotene is currently marketed for treatment of cutaneous T-cell lymphoma and there has been growing interest in its therapeutic effectiveness for other cancers. Neuroprotective effects of bexarotene have also been reported. In this study, a simple... Read More about Simple and sensitive HPLC-UV method for determination of bexarotene in rat plasma.