Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics

Talevi, Alan; Bellera, Carolina L.

doi:10.1080/17460441.2020.1704729

Cited by 209 publications

(148 citation statements)

References 23 publications

(29 reference statements)

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“…Vero E6 cells were seeded at a density of 1.5 × 10 5 Mice were weighed daily throughout the experiment, and dosages were adjusted accordingly.…”

Section: Inhibition Of Sars-cov-2 Virus In Cell-culturementioning

confidence: 99%

“…While side effects may be of particular concern for such treatments, another advantage of targeting host protein is the availability of many approved drugs against host proteins, allowing for drug repurposing. The main advantage of repurposing approved drugs is that they have already proven to be sufficiently safe, they have successfully passed clinical trials and regulatory scrutiny, and they have already undergone post-marketing surveillance (5).…”

Section: Introductionmentioning

confidence: 99%

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Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Vitner

Avraham

Achdout

et al. 2020

Preprint

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One Sentence Summary: An analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2. AbstractThe need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic.Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target.We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.

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“…Vero E6 cells were seeded at a density of 1.5 × 10 5 Mice were weighed daily throughout the experiment, and dosages were adjusted accordingly.…”

Section: Inhibition Of Sars-cov-2 Virus In Cell-culturementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Vitner

Avraham

Achdout

et al. 2020

Preprint

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“…There is a need to nd therapeutic interventions and to achieve this existing drugs can be repurposed (Schneider and Schneider, 2018;Cavalla et al, 2017) for treating the SARS-CoV-2 infection (Pandey, et al 2020) (Figure 1). Approximately one-third of drug approvals involve repurposed drugs (Talevi and Bellera, 2020). There is a broad range of choices which can curb the effects of viral infection and also prevent it.…”

Section: Repurposing Of Existing Drugs Against Sars-cov-2mentioning

confidence: 99%

Repurposing drugs for treatment of SARS-CoV-2 infection: Computational design insights into mechanisms of action

Kandwal

Fayne

2020

Preprint

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The COVID-19 pandemic has negatively affected human life globally. It has led to economic crises and health emergencies across the world, spreading rapidly among the human population and has caused many deaths. Currently, there are no treatments available for COVID-19 so there is an urgent need to develop therapeutic interventions that could be used against the novel coronavirus infection. In this research, we used computational drug design technologies to repurpose existing drugs as inhibitors of SARS-CoV-2 viral proteins. The Broad Institute’s Drug Repurposing Hub consists of in-development/approved drugs and was computationally screened to identify potential hits which could inhibit protein targets encoded by the SARS-CoV-2 genome. By virtually screening the Broad collection, using rationally designed pharmacophore features, we identified molecules which may be repurposed against viral nucleocapsid and non-structural proteins. The pharmacophore features were generated after careful visualisation of the interactions between co-crystalised ligands and the protein binding site. The ChEMBL database was used to determine the compound’s level of inhibition of SARS-CoV-2 and correlate the predicted viral protein target with whole virus in vitro data. The results from this study may help to accelerate drug development against COVID-19 and the hit compounds should be progressed through further in vitro and in vivo studies on SARS-CoV-2.

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“…As an alternative, drug repositioning has been considered, it refers to a new medical indication for an old drug that may currently be approved for another medical use (6). The advantages of this alterative are the reduction or elimination of drug development costs and the availability of comprehensive data on their pharmacology, formulation, safety and adverse effects (7). Potential disadvantages include handling patents, intellectual property, investment, market demand and even production technology (8).…”

Section: Introductionmentioning

confidence: 99%

Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning

et al. 2020

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The widespread dysregulation that characterizes cancer cells has been dissected and many regulation pathways common to multiple cancer types have been described in depth. Wnt/β-catenin signaling and autophagy are among these principal pathways, which contribute to tumor growth and resistance to anticancer therapies. Currently, several therapeutic strategies that target either Wnt/β-catenin signaling or autophagy are in various stages of development. Targeted therapies that block specific elements that participate in both pathways; are subject to in vitro studies as well as pre-clinical and early clinical trials. Strikingly, drugs designed for other diseases also impact these pathways, which is relevant since they are already FDA-approved and sometimes even routinely used in the clinic. The main focus of this mini-review is to highlight the importance of drug repositioning to inhibit the Wnt/β-catenin and autophagy pathways, with an emphasis on the interplay between them. The data we found strongly suggested that this field is worth further examination.

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Challenges and opportunities with drug repurposing: finding strategies to find alternative uses of therapeutics

Cited by 209 publications

References 23 publications

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

Repurposing drugs for treatment of SARS-CoV-2 infection: Computational design insights into mechanisms of action

Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning

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