Predicting unintended effects of drugs based on off-target tissue effects

Kim, Docyong; Lee, Jae-Hyun; Lee, Sunjae; Park, Junseok; Lee, Doheon

doi:10.1016/j.bbrc.2015.11.095

Cited by 19 publications

(14 citation statements)

References 12 publications

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“…These drugs are currently used for other medical purposes, indicating that they have already passed extensive toxicity testing. Therefore, we believe that further well-designed mechanistic animal studies and human trials including investigation of off-target tissue effects 39 could lead to the rapid development of potentially effective therapies for diabetic renal and cardiovascular diseases.…”

Section: Discussionmentioning

confidence: 99%

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications

Noh

Yu²,

Kim³

et al. 2017

Kidney International

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Macrophage activation is increased in diabetes and correlated with the onset and progression of vascular complications. To identify drugs that could inhibit macrophage activation, we developed a cell-based assay and screened a 1,040 compound library for anti-inflammatory effects. Beta2 adrenergic receptor (β2AR) agonists were identified as the most potent inhibitors of phorbol myristate acetate-induced tumor necrosis factor-α production in rat bone marrow macrophages. In peripheral blood mononuclear cells isolated from streptozotocin-induced diabetic rats, β2AR agonists inhibited diabetes-induced tumor necrosis factor-α production, which was prevented by co-treatment with a selective β2AR blocker. To clarify the underlying mechanisms, THP-1 cells and bone marrow macrophages were exposed to high glucose. High glucose reduced β-arrestin2, a negative regulator of NF-κB activation, and its interaction with IκBα. This subsequently enhanced phosphorylation of IκBα and activation of NF-κB. The β2AR agonists enhanced β-arrestin2 and its interaction with IκBα, leading to down-regulation of NF-κB. A siRNA specific for β-arrestin2 reversed β2AR agonist-mediated inhibition of NF-κB activation and inflammatory cytokine production. Treatment of Zucker Diabetic Fatty rats with a β2AR agonist for 12 weeks attenuated monocyte activation as well as pro-inflammatory and pro-fibrotic responses in the kidneys and heart. Thus, β2AR agonists might have protective effects against diabetic renal and cardiovascular complications.

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Section: Discussionmentioning

confidence: 99%

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications

Noh

Yu²,

Kim³

et al. 2017

Kidney International

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“…Gut hormone receptors are expressed in the gastrointestinal tract where also orally administrated drugs are absorbed to the circulatory. It was confirmed, e.g., in [13] that tissue expression and cellular localization of the potential off-target proteins play crucial role in occurrence of the associated drug side effects. That is why we believe that both, function and localization of gut hormone receptors are factors which make our computational study on the drug off-target interactions plausible.…”

Section: Introductionmentioning

confidence: 88%

“…Both, on and off-targets of simvastatin are alpha-helical transmembrane proteins but they differ in localization (endoplasmic reticulum vs. cellular membrane). The location of the intended molecular target (on-target) of a given drug in particular body tissues and organs (gut, liver, pancreas, CNS, blood vessels) is an important premise to trace its unintended targets (off-targets) and prevent associated side effects [13, 14]. For instance, a change of molecular targets from salt transporters to urea transporters which are expressed specifically in kidneys [15] could be a way to minimize side effects of diuretics [15].…”

Section: Introductionmentioning

confidence: 99%

Drug-induced diabetes type 2: In silico study involving class B GPCRs

et al. 2019

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A disturbance of glucose homeostasis leading to type 2 diabetes mellitus (T2DM) is one of the severe side effects that may occur during a prolonged use of many drugs currently available on the market. In this manuscript we describe the most common cases of drug-induced T2DM, discuss available pharmacotherapies and propose new ones. Among various pharmacotherapies of T2DM, incretin therapies have recently focused attention due to the newly determined crystal structure of incretin hormone receptor GLP1R. Incretin hormone receptors: GLP1R and GIPR together with the glucagon receptor GCGR regulate food intake and insulin and glucose secretion. Our study showed that incretin hormone receptors, named also gut hormone receptors as they are expressed in the gastrointestinal tract, could potentially act as unintended targets (off-targets) for orally administrated drugs. Such off-target interactions, depending on their effect on the receptor (stimulation or inhibition), could be beneficial, like in the case of incretin mimetics, or unwanted if they cause, e.g., decreased insulin secretion. In this in silico study we examined which well-known pharmaceuticals could potentially interact with gut hormone receptors in the off-target way. We observed that drugs with the strongest binding affinity for gut hormone receptors were also reported in the medical information resources as the least disturbing the glucose homeostasis among all drugs in their class. We suggested that those strongly binding molecules could potentially stimulate GIPR and GLP1R and/or inhibit GCGR which could lead to increased insulin secretion and decreased hepatic glucose production. Such positive effect on the glucose homeostasis could compensate for other, adverse effects of pharmacotherapy which lead to drug-induced T2DM. In addition, we also described several top hits as potential substitutes of peptidic incretin mimetics which were discovered in the drug repositioning screen using gut hormone receptors structures against the ZINC15 compounds subset.

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“…Singh & Lillard, 2009). Delivery of drug to nontarget tissues can result in a range of complications, ranging from mild discomfort to life threating side effects (Kim, Lee, Lee, Park, & Lee, 2016). To solve this problem, nanoparticle-based drug delivery systems are being developed to improve the therapeutic index of drugs.…”

Section: Introductionmentioning

confidence: 99%

Use of magnetic fields and nanoparticles to trigger drug release and improve tumor targeting

Liu

Jang

Issadore

et al. 2019

WIREs Nanomed Nanobiotechnol

151

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Drug delivery strategies aim to maximize a drug's therapeutic index by increasing the concentration of drug at target sites while minimizing delivery to off‐target tissues. Because biological tissues are minimally responsive to magnetic fields, there has been a great deal of interest in using magnetic nanoparticles in combination with applied magnetic fields to selectively control the accumulation and release of drug in target tissues while minimizing the impact on surrounding tissue. In particular, spatially variant magnetic fields have been used to encourage accumulation of drug‐loaded magnetic nanoparticles at target sites, while time‐variant magnetic fields have been used to induce drug release from thermally sensitive nanocarriers. In this review, we discuss nanoparticle formulations and approaches that have been developed for magnetic targeting and/or magnetically induced drug release, as well as ongoing challenges in using magnetism for therapeutic applications. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

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Predicting unintended effects of drugs based on off-target tissue effects

Cited by 19 publications

References 12 publications

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications

Beta 2-adrenergic receptor agonists are novel regulators of macrophage activation in diabetic renal and cardiovascular complications

Drug-induced diabetes type 2: In silico study involving class B GPCRs

Use of magnetic fields and nanoparticles to trigger drug release and improve tumor targeting

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