A Two-Tiered In Vitro Approach to De-Risk Drug Candidates for Potential Bile Salt Export Pump Inhibition Liabilities in Drug Discovery

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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Cholestatic Potential of Troglitazone as a Possible Factor Contributing to Troglitazone-Induced Hepatotoxicity: In Vivo and in Vitro Interaction at the Canalicular Bile Salt Export Pump (Bsep) in the Rat

Molecular Pharmacology ◽

10.1124/mol.59.3.627 ◽

2001 ◽

Vol 59 (3) ◽

pp. 627-635 ◽

Cited By ~ 220

Author(s):

Christoph Funk ◽

Christiane Ponelle ◽

Gerd Scheuermann ◽

Michael Pantze

Keyword(s):

Bile Salt ◽

Bile Salt Export Pump ◽

Canalicular Bile ◽

In Vitro Interaction

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Pharmacological premature termination codon readthrough of ABCB11 in bile salt export pump deficiency: an in vitro study

Hepatology ◽

10.1002/hep.31476 ◽

2020 ◽

Author(s):

Rachida Amzal ◽

Alice Thébaut ◽

Martine Lapalus ◽

Marion Almes ◽

Brigitte Grosse ◽

...

Keyword(s):

Bile Salt ◽

Premature Termination ◽

In Vitro Study ◽

Premature Termination Codon ◽

Vitro Study ◽

Termination Codon ◽

Bile Salt Export Pump

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Boosting Drug Discovery for Parkinson’s: Enhancement of the Delivery of a Monoamine Oxidase-B Inhibitor by Brain-Targeted PEGylated Polycaprolactone-Based Nanoparticles

Pharmaceutics ◽

10.3390/pharmaceutics11070331 ◽

2019 ◽

Vol 11 (7) ◽

pp. 331 ◽

Cited By ~ 2

Author(s):

Miguel Pinto ◽

Carlos Fernandes ◽

Eva Martins ◽

Renata Silva ◽

Sofia Benfeito ◽

...

Keyword(s):

Drug Discovery ◽

Monoamine Oxidase ◽

Polymeric Nanoparticles ◽

Symptomatic Relief ◽

In Vitro Models ◽

Monoamine Oxidase B ◽

Mao B ◽

Drug Candidates ◽

Poly Caprolactone

The current pharmacological treatments for Parkinson’s disease only offer symptomatic relief to the patients and are based on the administration of levodopa and catechol-O-methyltransferase or monoamine oxidase-B inhibitors (IMAO-B). Since the majority of drug candidates fail in pre- and clinical trials, due largely to bioavailability pitfalls, the use of polymeric nanoparticles (NPs) as drug delivery systems has been reported as an interesting tool to increase the stealth capacity of drugs or help drug candidates to surpass biological barriers, among other benefits. Thus, a novel potent, selective, and reversible IMAO-B (chromone C27, IC50 = 670 ± 130 pM) was encapsulated in poly(caprolactone) (PCL) NPs by a nanoprecipitation process. The resulting C27-loaded PEGylated PCL NPs (~213 nm) showed high stability and no cytotoxic effects in neuronal (SH-SY5Y), epithelial (Caco-2), and endothelial (hCMEC/D3) cells. An accumulation of PEGylated PCL NPs in the cytoplasm of SH-SY5Y and hCMEC/D3 cells was also observed, and their permeation across Caco-2 and hCMEC/D3 cell monolayers, used as in vitro models of the human intestine and blood-brain barrier, respectively, was demonstrated. PEGylated PCL NPs delivered C27 at concentrations higher than the MAO-B IC50 value, which provides evidence of their relevance to solving the drug discovery pitfalls.

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Drug Discovery by Drug Repurposing: Combating COVID-19 in the 21st Century

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557520999200824103803 ◽

2020 ◽

Vol 20 ◽

Cited By ~ 1

Author(s):

Nitesh Sanghai ◽

Kashfia Shafiq ◽

Geoffrey K. Tranmer

Keyword(s):

Drug Discovery ◽

Drug Repurposing ◽

Compassionate Use ◽

Drug Candidates ◽

Working Day ◽

Novel Coronavirus ◽

Approved Drugs ◽

Day By Day ◽

Potential Use

: Due to the rapidly developing nature of the current COVID-19 outbreak and its almost immediate humanitarian and economic toll, coronavirus drug discovery efforts have largely focused on generating potential COVID-19 drug candidates as quickly as possible. Globally, scientists are working day and night to find the best possible solution to treat the deadly virus. During the first few months of 2020, the SARS-CoV-2 outbreak quickly developed into a pandemic, with a mortality rate that was increasing at an exponential rate day by day. As a result, scientists have turned to a drug repurposing approach, to rediscover the potential use and benefits of existing approved drugs. Currently, there is no single drug approved by the U.S. Food and Drug Administration (FDA), for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV) that causes COVID-19. Based on only in-vitro studies, several active drugs are already in the clinical pipeline, made possible by following the compassionate use of medicine protocols. This method of repurposing and the use of existing molecules like Remdesivir (GS-5734), Chloroquine, Hydroxychloroquine, etc. has proven to be a landmark in the field of drug rediscovery. In this review article we will discuss the repurposing of medicines for treating the deadly novel coronavirus (SARS-CoV-2).

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Cytochrome P450 enzymes: a review on drug metabolizing enzyme inhibition studies in drug discovery and development

Bioanalysis ◽

10.4155/bio-2021-0132 ◽

2021 ◽

Vol 13 (17) ◽

pp. 1355-1378

Author(s):

Siva Nageswara Rao Gajula ◽

Megha Sajakumar Pillai ◽

Gananadhamu Samanthula ◽

Rajesh Sonti

Keyword(s):

Cytochrome P450 ◽

Drug Discovery ◽

Enzyme Inhibition ◽

In Vitro Study ◽

Cytochrome P450 Enzymes ◽

Drug Discovery And Development ◽

Drug Candidates ◽

Cyp Enzymes ◽

Cyp Inhibition

Assessment of drug candidate's potential to inhibit cytochrome P450 (CYP) enzymes remains crucial in pharmaceutical drug discovery and development. Both direct and time-dependent inhibition of drug metabolizing CYP enzymes by the concomitant administered drug is the leading cause of drug–drug interactions (DDIs), resulting in the increased toxicity of the victim drug. In this context, pharmaceutical companies have grown increasingly diligent in limiting CYP inhibition liabilities of drug candidates in the early stages and examining risk assessments throughout the drug development process. This review discusses different strategies and decision-making processes for assessing the drug–drug interaction risks by enzyme inhibition and lays particular emphasis on in vitro study designs and interpretation of CYP inhibition data in a stage-appropriate context.

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Can Bile Salt Export Pump Inhibition Testing in Drug Discovery and Development Reduce Liver Injury Risk? An International Transporter Consortium Perspective

Clinical Pharmacology & Therapeutics ◽

10.1002/cpt.1222 ◽

2018 ◽

Vol 104 (5) ◽

pp. 916-932 ◽

Cited By ~ 28

Author(s):

J. Gerry Kenna ◽

Kunal S. Taskar ◽

Christina Battista ◽

David L. Bourdet ◽

Kim L.R. Brouwer ◽

...

Keyword(s):

Drug Discovery ◽

Liver Injury ◽

Bile Salt ◽

Injury Risk ◽

Bile Salt Export Pump ◽

Drug Discovery And Development

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The ESCRT-III molecules regulate the apical targeting of bile salt export pump

Journal of Biomedical Science ◽

10.1186/s12929-020-00706-2 ◽

2021 ◽

Vol 28 (1) ◽

Author(s):

Shang-Hsin Wu ◽

Mei-Hwei Chang ◽

Ya-Hui Chen ◽

Hui-Lin Wu ◽

Huey-Huey Chua ◽

...

Keyword(s):

Bile Salt ◽

Fetal Liver ◽

Hepatoma Cell ◽

Temperature Shift ◽

Multivesicular Body ◽

Bile Salt Export Pump ◽

Body Protein ◽

Hepatoma Cell Lines

Abstract Background The bile salt export pump (BSEP) is a pivotal apical/canalicular bile salt transporter in hepatocytes that drives the bile flow. Defects in BSEP function and canalicular expression could lead to a spectrum of cholestatic liver diseases. One prominent manifestation of BSEP-associated cholestasis is the defective canalicular localization and cytoplasmic retention of BSEP. However, the etiology of impaired BSEP targeting to the canalicular membrane is not fully understood. Our goal was to discover what molecule could interact with BSEP and affect its post-Golgi sorting. Methods The human BSEP amino acids (a.a.) 491-630 was used as bait to screen a human fetal liver cDNA library through yeast two-hybrid system. We identified a BSEP-interacting candidate and showed the interaction and colocalization in the co-immunoprecipitation in hepatoma cell lines and histological staining in human liver samples. Temperature shift assays were used to study the post-Golgi trafficking of BSEP. We further determine the functional impacts of the BSEP-interacting candidate on BSEP in vitro. A hydrodynamically injected mouse model was established for in vivo characterizing the long-term impacts on BSEP. Results We identified that charged multivesicular body protein 5 (CHMP5), a molecule of the endosomal protein complex required for transport subcomplex-III (ESCRT-III), interacted and co-localized with BSEP in the subapical compartments (SACs) in developing human livers. Cholestatic BSEP mutations in the CHMP5-interaction region have defects in canalicular targeting and aberrant retention at the SACs. Post-Golgi delivery of BSEP and bile acid secretion were impaired in ESCRT-III perturbation or CHMP5-knockdown hepatic cellular and mouse models. This ESCRT-III-mediated BSEP sorting preceded Rab11A-regulated apical cycling of BSEP. Conclusions Our results showed the first example that ESCRT-III is essential for canalicular trafficking of apical membrane proteins, and provide new targets for therapeutic approaches in BSEP associated cholestasis.

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