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Fulltext Uncovering drug repurposing candidates for head and neck cancers: insights from systematic pharmacogenomics data analysis

Chai AWY, Tan AC, Cheong SC

Sci Rep, 2021 12 14;11(1):23933.
PMID: 34907286 DOI: 10.1038/s41598-021-03418-1

Effective treatment options for head and neck squamous cell carcinoma (HNSCC) are currently lacking. We exploited the drug response and genomic data of the 28 HNSCC cell lines, screened with 4,518 compounds, from the PRISM repurposing dataset to uncover repurposing drug candidates for HNSCC. A total of 886 active compounds, comprising of 418 targeted cancer, 404 non-oncology, and 64 chemotherapy compounds were identified for HNSCC. Top classes of mechanism of action amongst targeted cancer compounds included PI3K/AKT/MTOR, EGFR, and HDAC inhibitors. We have shortlisted 36 compounds with enriched killing activities for repurposing in HNSCC. The integrative analysis confirmed that the average expression of EGFR ligands (AREG, EREG, HBEGF, TGFA, and EPGN) is associated with osimertinib sensitivity. Novel putative biomarkers of response including those involved in immune signalling and cell cycle were found to be associated with sensitivity and resistance to MEK inhibitors respectively. We have also developed an RShiny webpage facilitating interactive visualization to fuel further hypothesis generation for drug repurposing in HNSCC. Our study provides a rich reference database of HNSCC drug sensitivity profiles, affording an opportunity to explore potential biomarkers of response in prioritized drug candidates. Our approach could also reveal insights for drug repurposing in other cancers.

Matched MeSH terms: Drug Repositioning*
Fulltext Transcriptomics-driven drug repositioning for the treatment of diabetic foot ulcer

Adikusuma W, Zakaria ZA, Irham LM, Nopitasari BL, Pradiningsih A, Firdayani F, et al.

Sci Rep, 2023 Jun 20;13(1):10032.
PMID: 37340026 DOI: 10.1038/s41598-023-37120-1

Diabetic foot ulcers (DFUs) are a common complication of diabetes and can lead to severe disability and even amputation. Despite advances in treatment, there is currently no cure for DFUs and available drugs for treatment are limited. This study aimed to identify new candidate drugs and repurpose existing drugs to treat DFUs based on transcriptomics analysis. A total of 31 differentially expressed genes (DEGs) were identified and used to prioritize the biological risk genes for DFUs. Further investigation using the database DGIdb revealed 12 druggable target genes among 50 biological DFU risk genes, corresponding to 31 drugs. Interestingly, we highlighted that two drugs (urokinase and lidocaine) are under clinical investigation for DFU and 29 drugs are potential candidates to be repurposed for DFU therapy. The top 5 potential biomarkers for DFU from our findings are IL6ST, CXCL9, IL1R1, CXCR2, and IL10. This study highlights IL1R1 as a highly promising biomarker for DFU due to its high systemic score in functional annotations, that can be targeted with an existing drug, Anakinra. Our study proposed that the integration of transcriptomic and bioinformatic-based approaches has the potential to drive drug repurposing for DFUs. Further research will further examine the mechanisms by which targeting IL1R1 can be used to treat DFU.

Matched MeSH terms: Drug Repositioning
Fulltext The antineoplastic properties of FTY720: evidence for the repurposing of fingolimod

Patmanathan SN, Yap LF, Murray PG, Paterson IC

J Cell Mol Med, 2015 Oct;19(10):2329-40.
PMID: 26171944 DOI: 10.1111/jcmm.12635

Almost all drugs approved for use in humans possess potentially beneficial 'off-target' effects in addition to their principal activity. In some cases this has allowed for the relatively rapid repurposing of drugs for other indications. In this review we focus on the potential for re-purposing FTY720 (also known as fingolimod, Gilenya(™)), an immunomodulatory drug recently approved for the treatment of multiple sclerosis (MS). The therapeutic benefit of FTY720 in MS is largely attributed to the immunosuppressive effects that result from its modulation of sphingosine 1-phosphate receptor signalling. However, this drug has also been shown to inhibit other cancer-associated signal transduction pathways in part because of its structural similarity to sphingosine, and consequently shows efficacy as an anti-cancer agent both in vitro and in vivo. Here, we review the effects of FTY720 on signal transduction pathways and cancer-related cellular processes, and discuss its potential use as an anti-cancer drug.

Matched MeSH terms: Drug Repositioning*
Fulltext Repurposing Antimalarials to Tackle the COVID-19 Pandemic

Krishna S, Augustin Y, Wang J, Xu C, Staines HM, Platteeuw H, et al.

Trends Parasitol, 2021 01;37(1):8-11.
PMID: 33153922 DOI: 10.1016/j.pt.2020.10.003

Artemisinin-based combination therapies (ACTs) have demonstrated in vitro inhibition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Artemisinins have also shown anti-inflammatory effects, including inhibition of interleukin-6 (IL-6) that plays a key role in the development of severe coronavirus disease 2019 (COVID-19). There is now sufficient evidence for the effectiveness of ACTs, and in particular artesunate/pyronaridine, to support clinical studies for COVID-19 infections.

Matched MeSH terms: Drug Repositioning*
Diverse effects of clarithromycin and proposal of its clinical application for treating COVID-19 as a repurposing drug

Takemori N, Ooi HK, Imai G, Saio M

Trop Biomed, 2021 Sep 01;38(3):343-352.
PMID: 34508342 DOI: 10.47665/tb.38.3.077

Outbreak of SARS-CoV-2 has been declared a pandemic, which is a serious threat to human health. The disease was named coronavirus disease 2019 (COVID-19). Until now, several vaccines and a few drugs have been approved for the prevention and treatment for COVID-19. Recently, the effect of some macrolides including clarithromycin (CAM) on COVID-19 has attracted attention. CAM is known to have diverse effects including immunomodulatory and immunosuppressive effects, autophagy inhibition, steroid sparing effect, reversibility of drug resistance, antineoplastic effect, antiviral effect as well as bacteriostatic/bactericidal effect. Many patients with COVID-19 died due to an overwhelming response of their own immune system characterized by the uncontrolled release of circulating inflammatory cytokines (cytokine release syndrome [CRS]). This CRS plays a major role in progressing pneumonia to acute respiratory distress syndrome (ARDS) in COVID-19 patients. It is noteworthy that CAM can suppress inflammatory cytokines responsible for CRS and also has anti-SARS-CoV-2 effect. Considering the rapidly progressive global disease burden of COVID 19, the application of CAM for treating COVID-19 needs to be urgently evaluated. Recently, an open-labeled non-randomized trial using CAM for treating COVID-19 (ACHIEVE) was initiated in Greece in May, 2020. Its results, though preprint, indicated that CAM treatment of patients with moderate COVID-19 was associated with early clinical improvement and containment of viral load. Thus, treatment with CAM as a single agent or combined with other anti-SARS CoV-2 drugs should be tried for treating COVID-19. In this article, we discussed the significance and usefulness of CAM in treating COVID-19.

Matched MeSH terms: Drug Repositioning*
Repurposing Antihypertensive Drugs for the Management of Alzheimer's Disease

Law CSW, Yeong KY

Curr Med Chem, 2021;28(9):1716-1730.
PMID: 32164502 DOI: 10.2174/0929867327666200312114223

Alzheimer's disease (AD) is a neurodegenerative disorder that has affected millions of people worldwide. However, currently, there is no treatment to cure the disease. The AD drugs available in the market only manage the disease symptomatically and the effects are usually short-term. Thus, there is a need to look at alternatives AD therapies. This literature review aims to shed some light on the potential of repurposing antihypertensives to treat AD. Mid-life hypertension has not only been recognised as a risk factor for AD, but its relation with AD has also been well established. Hence, antihypertensives were postulated to be beneficial in managing AD. Four classes of antihypertensives, as well as their potential limitations and prospects in being utilised as AD therapeutics, were discussed in this review.

Matched MeSH terms: Drug Repositioning
Repurposing FDA-approved drugs as HIV-1 integrase inhibitors: an in silico investigation

Ha CHX, Lee NK, Rahman T, Hwang SS, Yam WK, Chee XW

J Biomol Struct Dyn, 2023 Apr;41(6):2146-2159.
PMID: 35067186 DOI: 10.1080/07391102.2022.2028677

The Human Immunodeficiency Virus (HIV) infection is a global pandemic that has claimed 33 million lives to-date. One of the most efficacious treatments for naïve or pretreated HIV patients is the HIV integrase strand transfer inhibitors (INSTIs). However, given that HIV treatment is life-long, the emergence of HIV strains resistant to INSTIs is an imminent challenge. In this work, we showed two best regression QSAR models that were constructed using a boosted Random Forest algorithm (r2 = 0.998, q210CV = 0.721, q2external_test = 0.754) and a boosted K* algorithm (r2 = 0.987, q210CV = 0.721, q2external_test = 0.758) to predict the pIC50 values of INSTIs. Subsequently, the regression QSAR models were deployed against the Drugbank database for drug repositioning. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies and accelerated Molecular Dynamics simulation. Lastly, their potential as INSTIs were also evaluated from our literature search. Our study offers the first example of a large-scale regression QSAR modelling effort for discovering highly active INSTIs to combat HIV infection.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Drug Repositioning
Fulltext Drug Discovery of Spinal Muscular Atrophy (SMA) from the Computational Perspective: A Comprehensive Review

Chong LC, Gandhi G, Lee JM, Yeo WWY, Choi SB

Int J Mol Sci, 2021 Aug 20;22(16).
PMID: 34445667 DOI: 10.3390/ijms22168962

Spinal muscular atrophy (SMA), one of the leading inherited causes of child mortality, is a rare neuromuscular disease arising from loss-of-function mutations of the survival motor neuron 1 (SMN1) gene, which encodes the SMN protein. When lacking the SMN protein in neurons, patients suffer from muscle weakness and atrophy, and in the severe cases, respiratory failure and death. Several therapeutic approaches show promise with human testing and three medications have been approved by the U.S. Food and Drug Administration (FDA) to date. Despite the shown promise of these approved therapies, there are some crucial limitations, one of the most important being the cost. The FDA-approved drugs are high-priced and are shortlisted among the most expensive treatments in the world. The price is still far beyond affordable and may serve as a burden for patients. The blooming of the biomedical data and advancement of computational approaches have opened new possibilities for SMA therapeutic development. This article highlights the present status of computationally aided approaches, including in silico drug repurposing, network driven drug discovery as well as artificial intelligence (AI)-assisted drug discovery, and discusses the future prospects.

Matched MeSH terms: Drug Repositioning/methods; Drug Repositioning/trends
Fulltext Surgical repositioning of an impacted and dilacerated central incisor: A case report

Venkiteswaran, Annapurny, Ha, Kien Onn

Compendium of Oral Science, 2016;3(1):33-37.
MyJurnal

This case report describes the management of an impacted and dilacerated upper permanent incisor in an 11 year old girl who also presented with a congenitally missing lateral incisor in the same quadrant. The two treatment options commonly chosen for the management of an impacted incisor are surgical exposure followed by orthodontic traction and extraction of the tooth itself. This case posed an extra challenge as the adjacent lateral incisor was congenitally missing. Instead of resorting to the use of dentures, an alternative treatment involving the surgical repositioning of the impacted tooth was done. This method not only satisfied the patient’s aesthetic requirement but ensured preservation of alveolar bone height and thickness in the upper anterior segment. Surgical repositioning of an impacted and/or dilacerated tooth can be considered as an alternative treatment option when surgical exposure and traction of the tooth is not possible.

Matched MeSH terms: Drug Repositioning
Fulltext Spontaneous repositioning of posterior chamber intraocular lens: a mere coincidence?

Wern-Yih C, Jan-Bond C, Sudha M, Norlelawati A, Shatriah I

Arq Bras Oftalmol, 2020 08;83(4):329-331.
PMID: 32756777 DOI: 10.5935/0004-2749.20200054

Despite the recent developments in modern cataract surgery and the application of a vast array of new devices and machines, late in-the-bag intraocular lens dislocation remains a devastating, albeit rare, complication. Various nonsurgical and surgical techniques have been used to manage this complication. We report a case of spontaneous repositioning in the left eye of an anteriorly subluxated in-the-bag intraocular lens. The spontaneous repositioning may have been caused by antagonistic effects related to the topical administration of brimonidine and prednisolone. The dislocation was treated without aggressive manipulation or surgical intervention.

Matched MeSH terms: Drug Repositioning
In silico prediction of potential inhibitors for SARS-CoV-2 Omicron variant using molecular docking and dynamics simulation-based drug repurposing

Mohamed EAR, Abdel-Rahman IM, Zaki MEA, Al-Khdhairawi A, Abdelhamid MM, Alqaisi AM, et al.

J Mol Model, 2023 Feb 20;29(3):70.
PMID: 36808314 DOI: 10.1007/s00894-023-05457-z

BACKGROUND: In November 2021, variant B.1.1.529 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was identified by the World Health Organization (WHO) and designated Omicron. Omicron is characterized by a high number of mutations, thirty-two in total, making it more transmissible than the original virus. More than half of those mutations were found in the receptor-binding domain (RBD) that directly interacts with human angiotensin-converting enzyme 2 (ACE2). This study aimed to discover potent drugs against Omicron, which were previously repurposed for coronavirus disease 2019 (COVID-19). All repurposed anti-COVID-19 drugs were compiled from previous studies and tested against the RBD of SARS-CoV-2 Omicron.
METHODS: As a preliminary step, a molecular docking study was performed to investigate the potency of seventy-one compounds from four classes of inhibitors. The molecular characteristics of the best-performing five compounds were predicted by estimating the drug-likeness and drug score. Molecular dynamics simulations (MD) over 100 ns were performed to inspect the relative stability of the best compound within the Omicron receptor-binding site.
RESULTS: The current findings point out the crucial roles of Q493R, G496S, Q498R, N501Y, and Y505H in the RBD region of SARS-CoV-2 Omicron. Raltegravir, hesperidin, pyronaridine, and difloxacin achieved the highest drug scores compared with the other compounds in the four classes, with values of 81%, 57%, 18%, and 71%, respectively. The calculated results showed that raltegravir and hesperidin had high binding affinities and stabilities to Omicron with ΔGbinding of - 75.7304 ± 0.98324 and - 42.693536 ± 0.979056 kJ/mol, respectively. Further clinical studies should be performed for the two best compounds from this study.

Matched MeSH terms: Drug Repositioning
Beyond lipid-lowering: role of statins in endometrial cancer

Hafizz AMHA, Zin RRM, Aziz NHA, Kampan NC, Shafiee MN

Mol Biol Rep, 2020 Oct;47(10):8199-8207.
PMID: 32897522 DOI: 10.1007/s11033-020-05760-5

As the obesity rates dramatically increased across the globe, the risk of endometrial cancer (EC) has substantially increased. Measures to improve the EC outcome is utmost important, especially data have shown that women at their reproductive age are commonly affected. No doubt, surgical intervention is a standard treatment for EC. However, the fact that this cancer could arise from metabolic diseases, additional therapy by lipid-lowering agent could be utilized to change the tumour environment. We review available evidence to support the use of this agent in the clinical setting. We search available evidence on the use of statin in EC, in various settings including cell lines, animal and human study. The possible actions at different molecular pathways leading to cellular changes and proliferation of cell were evaluated. The venture in drug repositioning of statins as a chemo-preventive potential agent in EC has gained attention in gynaecological oncology practice worldwide. Lipid-lowering effect by statins may exerted a chemoprotective effect in EC, but there is still lack of evidence on statins use to improve prognosis and survival in EC. Through the cholesterol-lowering effect of statins; theoretically, it could inhibit cell growth, proliferation, migration, and lead to apoptosis. Epidemiological studies suggested that statins may improve survival rate among EC patients. However, some evidence revealed the effects were only more prominent in type II EC. Notwithstanding that several studies also showed no benefit of statins in EC. Hence we highlight the limitations of these studies in this review. In line with recent literature on the topic, statins may play a role in EC management. Future studies for a proper systematic review and randomized controlled study are needed to answer some uncertainties of statins effect in EC.

Matched MeSH terms: Drug Repositioning*
Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview

Wen WX, Lee SY, Siang R, Koh RY

Adv Ther, 2017 06;34(6):1245-1269.
PMID: 28484954 DOI: 10.1007/s12325-017-0547-2

Fibrosis is a potentially debilitating disease with high morbidity rates. It is estimated that half of all deaths that occur in the USA are attributed to fibrotic disorders. Fibrotic disorders are characterized primarily by disruption in the extracellular matrix deposition and breakdown equilibrium, leading to the accumulation of excessive amounts of extracellular matrix. Given the potentially high prevalence of fibrosis and the paucity of agents currently available for the treatment of this disease, there is an urgent need for the identification of drugs that can be utilized to treat the disease. Pentoxifylline is a methylxanthine derivative that is currently approved for the treatment of vascular diseases, in particular, claudication. Pentoxifylline has three main properties: improving the rheological properties of blood, anti-inflammatory, and antioxidative. Recently, the effectiveness of pentoxifylline in the treatment of fibrosis via attenuating and reversing fibrotic lesions has been demonstrated in several clinical trials and animal studies. As a result of the limited availability of antifibrotic agents in the long-term treatment of fibrosis that can attenuate and even reverse fibrotic lesions effectively, it would be of particular importance to consider the potential clinical utility of pentoxifylline in the treatment of fibrosis. Thus, this paper discusses the evolving roles of pentoxifylline in the treatment of different types of fibrosis.

Matched MeSH terms: Drug Repositioning*
Potential of repurposing chloroquine as an adjunct therapy for melioidosis based on a murine model of Burkholderia pseudomallei infection

Ganesan N, Embi N, Hasidah MS

Trop Biomed, 2020 Jun 01;37(2):303-317.
PMID: 33612800

Burkholderia pseudomallei is the etiologic agent of melioidosis, a major cause of community-acquired pneumonia and sepsis in the endemic areas. The overall mortality of patients with severe melioidosis remains high due to severe sepsis attributed to overwhelming inflammatory cytokine response in spite of recommended antibiotic therapy. It is crucial that therapeutic approaches beyond just effective antibiotic treatment such as adjunct therapy be considered to mitigate the dysregulated inflammatory signaling and augment host defenses. In an acute B. pseudomallei infection model, we have previously demonstrated that treatment with anti-malarial drug, chloroquine, modulated inflammatory cytokine levels and increased animal survivability via Akt-mediated inhibition of glycogen synthase kinase-3β (GSK3β). GSK3β is a downstream effector molecule within the phosphatidylinositol 3-kinase (PI3K)/ Akt axis which plays a pivotal role in regulating the production of pro- and anti-inflammatory cytokines. Here we evaluate the effect of chloroquine treatment in combination with a subtherapeutic dose of the antibiotic doxycycline on animal survivability, cytokine levels and phosphorylation states of GSK3β (Ser9) in a murine model of acute melioidosis infection to investigate whether chloroquine could be used as an adjunct therapy along with doxycycline for the treatment of melioidosis. Our findings revealed that 50 mg/kg b.w. chloroquine treatment together with a dose of 20 mg/kg b.w. doxycycline improved survivability (100%) of mice infected with 3 X LD50 of B. pseudomallei and significantly (P<0.05) lowered the bacterial loads in spleen, liver and blood compared to controls. B. pseudomallei-infected mice subjected to adjunct treatment with chloroquine and doxycycline significantly (P<0.05) reduced serum levels of pro-inflammatory cytokines (TNF-α, IFN-γ and IL-6) but increased levels of antiinflammatory cytokines (IL-4 and IL-10). Western blot analysis demonstrated that the intensities of pGSK3β (Ser9) in liver samples from mice treated with chloroquine and doxycycline combination were significantly (P<0.05) higher suggesting that the adjunct treatment resulted in significant inhibition of GSK3β. Taken together the bacteriostatic action of doxycycline coupled with the cytokine-modulating effect of chloroquine gave full protection to B. pseudomallei-infected mice and involved inhibition of GSK3β. Findings from the present study using B. pseudomallei-infected BALB/c mice suggest that chloroquine is a plausible candidate for repurposing as adjunct therapy to treat acute B. pseudomallei infection.

Matched MeSH terms: Drug Repositioning*
Fulltext Repositioning Ivermectin for Covid-19 treatment: Molecular mechanisms of action against SARS-CoV-2 replication

Low ZY, Yip AJW, Lal SK

Biochim Biophys Acta Mol Basis Dis, 2022 Feb 01;1868(2):166294.
PMID: 34687900 DOI: 10.1016/j.bbadis.2021.166294

Ivermectin (IVM) is an FDA approved macrocyclic lactone compound traditionally used to treat parasitic infestations and has shown to have antiviral potential from previous in-vitro studies. Currently, IVM is commercially available as a veterinary drug but have also been applied in humans to treat onchocerciasis (river blindness - a parasitic worm infection) and strongyloidiasis (a roundworm/nematode infection). In light of the recent pandemic, the repurposing of IVM to combat SARS-CoV-2 has acquired significant attention. Recently, IVM has been proven effective in numerous in-silico and molecular biology experiments against the infection in mammalian cells and human cohort studies. One promising study had reported a marked reduction of 93% of released virion and 99.98% unreleased virion levels upon administration of IVM to Vero-hSLAM cells. IVM's mode of action centres around the inhibition of the cytoplasmic-nuclear shuttling of viral proteins by disrupting the Importin heterodimer complex (IMPα/β1) and downregulating STAT3, thereby effectively reducing the cytokine storm. Furthermore, the ability of IVM to block the active sites of viral 3CLpro and S protein, disrupts important machinery such as viral replication and attachment. This review compiles all the molecular evidence to date, in review of the antiviral characteristics exhibited by IVM. Thereafter, we discuss IVM's mechanism and highlight the clinical advantages that could potentially contribute towards disabling the viral replication of SARS-CoV-2. In summary, the collective review of recent efforts suggests that IVM has a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2.

Matched MeSH terms: Drug Repositioning*
Fulltext Drug ReposER: a web server for predicting similar amino acid arrangements to known drug binding interfaces for potential drug repositioning

Ab Ghani NS, Ramlan EI, Firdaus-Raih M

Nucleic Acids Res, 2019 07 02;47(W1):W350-W356.
PMID: 31106379 DOI: 10.1093/nar/gkz391

A common drug repositioning strategy is the re-application of an existing drug to address alternative targets. A crucial aspect to enable such repurposing is that the drug's binding site on the original target is similar to that on the alternative target. Based on the assumption that proteins with similar binding sites may bind to similar drugs, the 3D substructure similarity data can be used to identify similar sites in other proteins that are not known targets. The Drug ReposER (DRug REPOSitioning Exploration Resource) web server is designed to identify potential targets for drug repurposing based on sub-structural similarity to the binding interfaces of known drug binding sites. The application has pre-computed amino acid arrangements from protein structures in the Protein Data Bank that are similar to the 3D arrangements of known drug binding sites thus allowing users to explore them as alternative targets. Users can annotate new structures for sites that are similarly arranged to the residues found in known drug binding interfaces. The search results are presented as mappings of matched sidechain superpositions. The results of the searches can be visualized using an integrated NGL viewer. The Drug ReposER server has no access restrictions and is available at http://mfrlab.org/drugreposer/.

Matched MeSH terms: Drug Repositioning/methods*; Drug Repositioning/statistics & numerical data
Fulltext Side chain similarity comparisons for integrated drug repositioning and potential toxicity assessments in epidemic response scenarios: The case for COVID-19

Ab Ghani NS, Emrizal R, Makmur H, Firdaus-Raih M

Comput Struct Biotechnol J, 2020;18:2931-2944.
PMID: 33101604 DOI: 10.1016/j.csbj.2020.10.013

Structures of protein-drug-complexes provide an atomic level profile of drug-target interactions. In this work, the three-dimensional arrangements of amino acid side chains in known drug binding sites (substructures) were used to search for similarly arranged sites in SARS-CoV-2 protein structures in the Protein Data Bank for the potential repositioning of approved compounds. We were able to identify 22 target sites for the repositioning of 16 approved drug compounds as potential therapeutics for COVID-19. Using the same approach, we were also able to investigate the potentially promiscuous binding of the 16 compounds to off-target sites that could be implicated in toxicity and side effects that had not been provided by any previous studies. The investigations of binding properties in disease-related proteins derived from the comparison of amino acid substructure arrangements allows for effective mechanism driven decision making to rank and select only the compounds with the highest potential for success and safety to be prioritized for clinical trials or treatments. The intention of this work is not to explicitly identify candidate compounds but to present how an integrated drug repositioning and potential toxicity pipeline using side chain similarity searching algorithms are of great utility in epidemic scenarios involving novel pathogens. In the case of the COVID-19 pandemic caused by the SARS-CoV-2 virus, we demonstrate that the pipeline can identify candidate compounds quickly and sustainably in combination with associated risk factors derived from the analysis of potential off-target site binding by the compounds to be repurposed.

Matched MeSH terms: Drug Repositioning
Fulltext Druggable targets of SARS-CoV-2 and treatment opportunities for COVID-19

Faheem, Kumar BK, Sekhar KVGC, Kunjiappan S, Jamalis J, Balaña-Fouce R, et al.

Bioorg Chem, 2020 Nov;104:104269.
PMID: 32947136 DOI: 10.1016/j.bioorg.2020.104269

COVID-19 caused by the novel SARS-CoV-2 has been declared a pandemic by the WHO is causing havoc across the entire world. As of May end, about 6 million people have been affected, and 367 166 have died from COVID-19. Recent studies suggest that the SARS-CoV-2 genome shares about 80% similarity with the SARS-CoV-1 while their protein RNA dependent RNA polymerase (RdRp) shares 96% sequence similarity. Remdesivir, an RdRp inhibitor, exhibited potent activity against SARS-CoV-2 in vitro. 3-Chymotrypsin like protease (also known as Mpro) and papain-like protease, have emerged as the potential therapeutic targets for drug discovery against coronaviruses owing to their crucial role in viral entry and host-cell invasion. Crystal structures of therapeutically important SARS-CoV-2 target proteins, namely, RdRp, Mpro, endoribonuclease Nsp15/NendoU and receptor binding domain of CoV-2 spike protein has been resolved, which have facilitated the structure-based design and discovery of new inhibitors. Furthermore, studies have indicated that the spike proteins of SARS-CoV-2 use the Angiotensin Converting Enzyme-2 (ACE-2) receptor for its attachment similar to SARS-CoV-1, which is followed by priming of spike protein by Transmembrane protease serine 2 (TMPRSS2) which can be targeted by a proven inhibitor of TMPRSS2, camostat. The current treatment strategy includes repurposing of existing drugs that were found to be effective against other RNA viruses like SARS, MERS, and Ebola. This review presents a critical analysis of druggable targets of SARS CoV-2, new drug discovery, development, and treatment opportunities for COVID-19.

Matched MeSH terms: Drug Repositioning
Drug repurposing for COVID-19: current evidence from randomized controlled adaptive platform trials and living systematic reviews

Augustin Y, Staines HM, Velavan TP, Kamarulzaman A, Kremsner PG, Krishna S

Br Med Bull, 2023 Sep 12;147(1):31-49.
PMID: 37312588 DOI: 10.1093/bmb/ldac037

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic resulted in a race to develop effective treatments largely through drug repurposing via adaptive platform trials on a global scale. Drug repurposing trials have focused on potential antiviral therapies aimed at preventing viral replication, anti-inflammatory agents, antithrombotic agents and immune modulators through a number of adaptive platform trials. Living systematic reviews have also enabled evidence synthesis and network meta-analysis as clinical trial data emerge globally.
SOURCES OF DATA: Recent published literature.
AREAS OF AGREEMENT: Corticosteroids and immunomodulators that antagonize the interleukin-6 (IL-6) receptor have been shown to play a critical role in modulating inflammation and improving clinical outcomes in hospitalized patients. Inhaled budesonide reduces the time to recovery in older patients with mild-to-moderate COVID-19 managed in the community.
AREAS OF CONTROVERSY: The clinical benefit of remdesivir remains controversial with conflicting evidence from different trials. Remdesivir led to a reduction in time to clinical recovery in the ACTT-1 trial. However, the World Health Organization SOLIDARITY and DISCOVERY trial did not find a significant benefit on 28-day mortality and clinical recovery.
GROWING POINTS: Other treatments currently being investigated include antidiabetic drug empagliflozin, antimalarial drug artesunate, tyrosine kinase inhibitor imatinib, immunomodulatory drug infliximab, antiviral drug favipiravir, antiparasitic drug ivermectin and antidepressant drug fluvoxamine.
AREAS TIMELY FOR DEVELOPING RESEARCH: The timing of therapeutic interventions based on postulated mechanisms of action and the selection of clinically meaningful primary end points remain important considerations in the design and implementation of COVID-19 therapeutic trials.

Matched MeSH terms: Drug Repositioning
The potential to treat lung cancer via inhalation of repurposed drugs

Lee WH, Loo CY, Ghadiri M, Leong CR, Young PM, Traini D

Adv Drug Deliv Rev, 2018 08;133:107-130.
PMID: 30189271 DOI: 10.1016/j.addr.2018.08.012

Lung cancer is a highly invasive and prevalent disease with ineffective first-line treatment and remains the leading cause of cancer death in men and women. Despite the improvements in diagnosis and therapy, the prognosis and outcome of lung cancer patients is still poor. This could be associated with the lack of effective first-line oncology drugs, formation of resistant tumors and non-optimal administration route. Therefore, the repurposing of existing drugs currently used for different indications and the introduction of a different method of drug administration could be investigated as an alternative to improve lung cancer therapy. This review describes the rationale and development of repositioning of drugs for lung cancer treatment with emphasis on inhalation. The review includes the current progress of repurposing non-cancer drugs, as well as current chemotherapeutics for lung malignancies via inhalation. Several potential non-cancer drugs such as statins, itraconazole and clarithromycin, that have demonstrated preclinical anti-cancer activity, are also presented. Furthermore, the potential challenges and limitations that might hamper the clinical translation of repurposed oncology drugs are described.

Matched MeSH terms: Drug Repositioning*

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