Drug repositioning: Progress and challenges in drug discovery for various diseases

Ye, Hua; Dai, Xiaowen; Xu, Yuan; Xing, Guomeng; Liu, Haichun; Lü, Tao; Chen, Yadong; Zhang, Yanmin

doi:10.1016/j.ejmech.2022.114239

Cited by 86 publications

(55 citation statements)

References 234 publications

(215 reference statements)

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“…A similar effect was observed by several compounds that selectively inhibit the TIM of T. vaginalis [5,6]. Additionally, the repurposing of drugs is an attractive pharmacological strategy for new therapeutics [7].…”

Section: Introductionsupporting

confidence: 63%

Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis

et al. 2022

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Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H2N-BZM6, O2N-BZM7, and O2N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O2N-BZM7 and O2N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies.

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Section: Introductionsupporting

confidence: 63%

Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis

et al. 2022

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“…Nevertheless, none of the studies clarified the mechanisms underlying the potential positive effects of these drugs on dysphagia, although a weak role of substance P (SP), a neuropeptide that enhances swallowing and cough reflexes, was hypothesized (Jin et al, 1994;Imoto et al, 2011;Canning et al, 2014). As many drugs have pleiotropic effects because of their interaction with multiple biological targets, known as primary and secondary effects (Jourdan et al, 2020;Hua et al, 2022), the process of finding new uses outside the original approved medical indication for existing drugs-i.e., redirecting, repurposing, repositioning and reprofiling (Kerber, 2003;Longman, 2004;Stuart, 2004), is increasing attention.…”

Section: Introductionmentioning

confidence: 99%

On the potential of drug repurposing in dysphagia treatment: New insights from a real-world pharmacovigilance study and a systematic review

Battini

Rocca²,

Guarnieri³

et al. 2023

Front. Pharmacol.

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Background: Polypharmacy is common in patients with dysphagia. Routinely used drugs may influence swallowing function either improving or worsening it. We aimed to explore the potential effects of three commonly used drug classes on dysphagia and aspiration pneumonia through a systematic review and a real-world data analysis to probe the possibility of drug repurposing for dysphagia treatment.Material and Methods: Five electronic databases were searched. Studies on adults at risk for dysphagia, treated with Dipeptidyl-Peptidase IV Inhibitors (DPP-4i), Adrenergic Beta-Antagonists (beta-blockers), or Angiotensin-Converting Enzyme Inhibitors (ACEi), and reporting outcomes on dysphagia or aspiration pneumonia were included. A nested case/non-case study was performed on adverse events recorded in the FDA Adverse Event Reporting System (FAERS) on patients >64 years. Cases (dysphagia or aspiration pneumonia) were compared between patients only treated with Levodopa and patients who were concomitantly treated with the drugs of interest.Results: Twenty studies were included in the review (17 on ACEi, 2 on beta-blockers, and 1 on DPP-4i). Contrasting findings on the effects of ACEi were found, with a protective effect mainly reported in Asian studies on neurological patients. Beta-blockers were associated with a reduced dysphagia rate. The study on DPP-4i suggested no effect on dysphagia and an increased risk of aspiration pneumonia. The FAERS analysis showed a reduction of the risk for dysphagia/aspiration pneumonia with ACEi, beta-blockers, and DPP-4i.Conclusion: Our study explores the potential drug repurposing of ACEi, beta-blockers and DPP-4i in neurological patients with dysphagia to improve swallowing function and reduce aspiration pneumonia risk. Future randomized controlled studies should confirm these results and clarify the underlying mechanisms of action.

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“…Compared with traditional de novo drug application, drug repurposing has become an effective alternative drug therapeutic strategy due to its lower risk of failure, reduce costs, and higher efficiency [ 212 ]. As shown in Table 2 , there are some examples of drug repurposing to target hypoxia signaling in cancer.…”

Section: Hif-1α/2α Inhibitors For Cancer Treatment In Clinical Studiesmentioning

confidence: 99%

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

et al. 2022

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Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.

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Drug repositioning: Progress and challenges in drug discovery for various diseases

Cited by 86 publications

References 234 publications

Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis

Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis

On the potential of drug repurposing in dysphagia treatment: New insights from a real-world pharmacovigilance study and a systematic review

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies

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