Front Pharmacol. 2021 Jun 30;12:617537. doi: 10.3389/fphar.2021.617537. eCollection 2021.

ABSTRACT

Background: Traditional therapeutics targeting Alzheimer's disease (AD)-related subpathologies have so far proved ineffective. Drug repurposing, a more effective strategy that aims to find new indications for existing drugs against other diseases, offers benefits in AD drug development. In this study, we aim to identify potential anti-AD agents through enrichment analysis of drug-induced transcriptional profiles of pathways based on AD-associated risk genes identified from genome-wide association analyses (GWAS) and single-cell transcriptomic studies. Methods: We systematically constructed four gene lists (972 risk genes) from GWAS and single-cell transcriptomic studies and performed functional and genes overlap analyses in Enrichr tool. We then used a comprehensive drug repurposing tool Gene2Drug by combining drug-induced transcriptional responses with the associated pathways to compute candidate drugs from each gene list. Prioritized potential candidates (eight drugs) were further assessed with literature review. Results: The genomic-based gene lists contain late-onset AD associated genes (BIN1, ABCA7, APOE, CLU, and PICALM) and clinical AD drug targets (TREM2, CD33, CHRNA2, PRSS8, ACE, TKT, APP, and GABRA1). Our analysis identified eight AD candidate drugs (ellipticine, alsterpaullone, tomelukast, ginkgolide A, chrysin, ouabain, sulindac sulfide and lorglumide), four of which (alsterpaullone, ginkgolide A, chrysin and ouabain) have shown repurposing potential for AD validated by their preclinical evidence and moderate toxicity profiles from literature. These support the value of pathway-based prioritization based on the disease risk genes from GWAS and scRNA-seq data analysis. Conclusion: Our analysis strategy identified some potential drug candidates for AD. Although the drugs still need further experimental validation, the approach may be applied to repurpose drugs for other neurological disorders using their genomic information identified from large-scale genomic studies.

PMID:34276354 | PMC:PMC8277916 | DOI:10.3389/fphar.2021.617537

Hum Mol Genet. 2021 Jul 19:ddab207. doi: 10.1093/hmg/ddab207. Online ahead of print.

ABSTRACT

Charcot-Marie-Tooth (CMT) disease is a neuropathy that lacks effective therapy. CMT patients show degeneration of peripheral nerves, leading to muscle weakness and loss of proprioception. Loss of mitochondrial oxidative phosphorylation proteins and enzymes of the antioxidant response accompany degeneration of nerves in skin biopsies of CMT patients. Herein, we followed a drug-repurposing approach to find drugs in an FDA-approved library that could prevent development of CMT disease in the Gdap1-null mouse model. We found that the antibiotic florfenicol is a mitochondrial uncoupler that prevents the production of reactive oxygen species and activates respiration in human GDAP1-knockdown neuroblastoma cells and in dorsal root ganglion neurons of Gdap1-null mice. Treatment of CMT-affected Gdap1-null mice with florfenicol has no beneficial effect in the course of the disease. However, administration of florfenicol, or the antioxidant MitoQ to pre-symptomatic GDAP1-null mice prevented weight gain and ameliorated the motor coordination deficiencies that developed in the Gdap1-null mice. Interestingly, both florfenicol and MitoQ halted the decay in mitochondrial and redox proteins in sciatic nerves of Gdap1-null mice supporting that oxidative damage is implicated in the etiology of the neuropathy. These findings support the development of clinical trials for translation of these drugs for treatment of CMT patients.

PMID:34274972 | DOI:10.1093/hmg/ddab207

Eur J Med Chem. 2021 Jul 13;224:113698. doi: 10.1016/j.ejmech.2021.113698. Online ahead of print.

ABSTRACT

Over recent years, many outbreaks caused by (re)emerging RNA viruses have been reported worldwide, including life-threatening Flaviviruses, such as Dengue (DENV) and Zika (ZIKV). Currently, there is only one licensed vaccine against Dengue, Dengvaxia®. However, its administration is not recommended for children under nine years. Still, there are no specific inhibitors available to treat these infectious diseases. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) is a metalloenzyme essential for viral replication, suggesting that it is a promising macromolecular target since it has no human homolog. Nowadays, several NS5 RdRp inhibitors have been reported, while none inhibitors are currently in clinical development. In this context, this review constitutes a comprehensive work focused on RdRp inhibitors from natural, synthetic, and even repurposing sources. Furthermore, their main aspects associated with the structure-activity relationship (SAR), proposed mechanisms of action, computational studies, and other topics will be discussed in detail.

PMID:34274831 | DOI:10.1016/j.ejmech.2021.113698

Curr Opin Chem Biol. 2021 Jul 15;65:74-84. doi: 10.1016/j.cbpa.2021.06.001. Online ahead of print.

ABSTRACT

Drug repurposing aims to find new uses for already existing and approved drugs. We now provide a brief overview of recent developments in drug repurposing using machine learning alongside other computational approaches for comparison. We also highlight several applications for cancer using kinase inhibitors, Alzheimer's disease as well as COVID-19.

PMID:34274565 | DOI:10.1016/j.cbpa.2021.06.001

Rev Endocr Metab Disord. 2021 Jul 17. doi: 10.1007/s11154-021-09675-9. Online ahead of print.

ABSTRACT

Developed as an antidiabetic drug, recent evidence suggests that several sodium-glucose co-transporter 2 inhibitors (SGLT2i), especially canagliflozin and dapagliflozin, may exhibit in vitro and in vivo anticancer activities in selected cancer types, including an inhibition of tumor growth and induction of cell death. When used in combination with chemotherapy or radiotherapy, SGLT2i may offer possible synergistic effects in enhancing their treatment efficacy while alleviating associated side effects. Potential mechanisms include a reduction of glucose uptake into cancer cells, systemic glucose restriction, modulation of multiple signaling pathways, and regulation of different gene and protein expression. Furthermore, preliminary clinical findings have reported potential anticancer properties of canagliflozin and dapagliflozin in patients with liver and colon cancers respectively, with reference to decreases in their tumor marker levels. Given its general tolerability and routine use in diabetes management, SGLT2i may be a good candidate for drug repurposing in cancer treatment and as adjunct to conventional therapies. While current evidence reveals that only certain SGLT2i appear to be effective against selected cancer types, further studies are needed to explore the antitumor abilities of each SGLT2i in various cancers. Moreover, clinical trials are called for to evaluate the safety and feasibility of introducing SGLT2i in the treatment regimen of patients with specific cancers, and to identify the preferred route of drug administration for targeted delivery to selected tumor sites.

PMID:34272645 | DOI:10.1007/s11154-021-09675-9

Comput Biol Chem. 2021 Jul 5;93:107536. doi: 10.1016/j.compbiolchem.2021.107536. Online ahead of print.

ABSTRACT

BACKGROUND: Discover possible Drug Target Interactions (DTIs) is a decisive step in the detection of the effects of drugs as well as drug repositioning. There is a strong incentive to develop effective computational methods that can effectively predict potential DTIs, as traditional DTI laboratory experiments are expensive, time-consuming, and labor-intensive. Some technologies have been developed for this purpose, however large numbers of interactions have not yet been detected, the accuracy of their prediction still low, and protein sequences and structured data are rarely used together in the prediction process.

METHODS: This paper presents DTIs prediction model that takes advantage of the special capacity of the structured form of proteins and drugs. Our model obtains features from protein amino-acid sequences using physical and chemical properties, and from drugs smiles (Simplified Molecular Input Line Entry System) strings using encoding techniques. Comparing the proposed model with different existing methods under K-fold cross validation, empirical results show that our model based on ensemble learning algorithms for DTI prediction provide more accurate results from both structures and features data.

RESULTS: The proposed model is applied on two datasets:Benchmark (feature only) datasets and DrugBank (Structure data) datasets. Experimental results obtained by Light-Boost and ExtraTree using structures and feature data results in 98 % accuracy and 0.97 f-score comparing to 94 % and 0.92 achieved by the existing methods. Moreover, our model can successfully predict more yet undiscovered interactions, and hence can be used as a practical tool to drug repositioning. A case study of applying our prediction model on the proteins that are known to be affected by Corona viruses in order to predict the possible interactions among these proteins and existing drugs is performed. Also, our model is applied on Covid-19 related drugs announced on DrugBank. The results show that some drugs like DB00691 and DB05203 are predicted with 100 % accuracy to interact with ACE2 protein. This protein is a self-membrane protein that enables Covid-19 infection. Hence, our model can be used as an effective tool in drug reposition to predict possible drug treatments for Covid-19.

PMID:34271420 | DOI:10.1016/j.compbiolchem.2021.107536

bioRxiv. 2021 Jul 5:2021.07.03.450938. doi: 10.1101/2021.07.03.450938. Preprint.

ABSTRACT

Drug development for specific antiviral agents against coronavirus disease 2019 (COVID-19) is still an unmet medical need as the pandemic continues to spread globally. Although huge efforts for drug repurposing and compound screens have put forth, only few compounds remain in late stage clinical trials. New approaches and assays are needed to accelerate COVID-19 drug discovery and development. Here we report a time-resolved fluorescence resonance energy transfer-based assay that detects the severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2) nucleocapsid protein (NP) produced in infected cells. It uses two specific anti-NP monoclonal antibodies (MAbs) conjugated to donor and acceptor fluorophores that produces a robust ratiometric signal for high throughput screening of large compound collections. Using this assay, we measured a half maximal inhibitory concentration (IC 50 ) for Remdesivir of 9.3 μM against infection with SARS-CoV-2 USA/WA1/2020 (WA-1). The assay also detected SARS-CoV-2 South African (Beta, β), Brazilian/Japanese variant P.1 (Gamma, γ), and Californian (Epsilon, ε), variants of concern or interest (VoC). Therefore, this homogeneous SARS-CoV-2 NP detection assay can be used for accelerating lead compound discovery for drug development and for evaluating drug efficacy against emerging SARS-CoV-2 VoC.

PMID:34268508 | PMC:PMC8282096 | DOI:10.1101/2021.07.03.450938

Cost Eff Resour Alloc. 2021 Jul 15;19(1):42. doi: 10.1186/s12962-021-00296-2.

ABSTRACT

BACKGROUND: A core evaluation framework that captures the health care and societal benefits of value added medicines (VAMs, also often called repurposed medicines) was proposed in Report 1, aiming to reduce the heterogeneity in value assessment processes across countries and to create incentives for manufacturers to invest into incremental innovation. However, this can be impactful only if the framework can be adapted to heterogeneous health care financing systems in different jurisdictions, and the cost of evidence generation necessitated by the framework takes into account the anticipated benefits for the health care system and rewards for the developers.

AREAS COVERED: The framework could potentially improve the pricing and reimbursement decisions of VAMs by adapting it to different country specific decision-contexts such as deliberative processes, augmented cost-effectiveness frameworks or formal multi-criteria decision analysis (MCDA); alternatively, some of its domains may be added to current general evaluation frameworks of medicines. The proposed evaluation framework may provide a starting point for practices based on which VAMs can be exempted from generic pricing mechanisms or can be integrated into the reimbursement and procurement system, allowing for price differentiation according to their added value. Besides evidence from RCTs, pricing and reimbursement decision processes of VAMs should allow for ex-ante non-RCT evidence for certain domains. Alternatively, relying on ex-post evidence agreements-such as outcome guarantee or coverage with evidence development-can also reduce decision uncertainty.

CONCLUSIONS: The core evaluation framework for VAMs could trigger changes in the existing pricing, reimbursement and procurement practices by improving the appraisal of the added value created by incremental innovation.

PMID:34266465 | DOI:10.1186/s12962-021-00296-2

J Basic Clin Physiol Pharmacol. 2021 Jul 15. doi: 10.1515/jbcpp-2020-0369. Online ahead of print.

ABSTRACT

OBJECTIVES: The new Coronavirus (SARS-CoV-2) created a pandemic in the world in late 2019 and early 2020. Unfortunately, despite the increasing prevalence of the disease, there is no effective drug for the treatment. A computational drug repurposing study would be an appropriate and rapid way to provide an effective drug in the treatment of the coronavirus disease of 2019 (COVID-19) pandemic. In this study, the inhibitory potential of more than 50 antiviral drugs on three important proteins of SARS-CoV-2, was investigated using the molecular docking method.

METHODS: By literature review, three important proteins, including main protease, RNA-dependent RNA polymerase (RdRp), and spike, were selected as the drug targets. The three-dimensional (3D) structure of protease, spike, and RdRp proteins was obtained from the Protein Data Bank. Proteins were energy minimized. More than 50 antiviral drugs were considered as candidates for protein inhibition, and their 3D structure was obtained from Drug Bank. Molecular docking settings were defined using Autodock 4.2 software and the algorithm was executed.

RESULTS: Based on the estimated binding energy of docking and hydrogen bond analysis and the position of drug binding, five drugs including, indinavir, lopinavir, saquinavir, nelfinavir, and remdesivir, had the highest inhibitory potential for all three proteins.

CONCLUSIONS: According to the results, among the mentioned drugs, saquinavir and lopinavir showed the highest inhibitory potential for all three proteins compared to the other drugs. This study suggests that saquinavir and lopinavir could be included in the laboratory phase studies as a two-drug treatment for SARS-CoV-2 inhibition.

PMID:34265888 | DOI:10.1515/jbcpp-2020-0369

Nanomedicine (Lond). 2021 Jul 15. doi: 10.2217/nnm-2021-0086. Online ahead of print.

ABSTRACT

While cancer remains a significant global health problem, advances in cancer biology, deep understanding of its underlaying mechanism and identification of specific molecular targets allowed the development of new therapeutic options. Drug repurposing poses several advantages as reduced cost and better safety compared with new compounds development. COX-2 inhibitors are one of the most promising drug classes for repurposing in cancer therapy. In this review, we provide an overview of the detailed mechanism and rationale of COX-2 inhibitors as anticancer agents and we highlight the most promising research efforts on nanotechnological approaches to enhance COX-2 inhibitors delivery with special focus on celecoxib as the most widely studied agent for chemoprevention or combined with chemotherapeutic and herbal drugs for combating various cancers.

PMID:34264123 | DOI:10.2217/nnm-2021-0086

Adv Exp Med Biol. 2021;1322:313-337. doi: 10.1007/978-981-16-0267-2_12.

ABSTRACT

Emerging and re-emerging viral diseases occur with regularity within the human population. The conventional 'one drug, one virus' paradigm for antivirals does not adequately allow for proper preparedness in the face of unknown future epidemics. In addition, drug developers lack the financial incentives to work on antiviral drug discovery, with most pharmaceutical companies choosing to focus on more profitable disease areas. Safe-in-man broad spectrum antiviral agents (BSAAs) can help meet the need for antiviral development by already having passed phase I clinical trials, requiring less time and money to develop, and having the capacity to work against many viruses, allowing for a speedy response when unforeseen epidemics arise. In this chapter, we discuss the benefits of repurposing existing drugs as BSAAs, describe the major steps in safe-in-man BSAA drug development from discovery through clinical trials, and list several database resources that are useful tools for antiviral drug repositioning.

PMID:34258746 | DOI:10.1007/978-981-16-0267-2_12

Adv Exp Med Biol. 2021;1322:195-218. doi: 10.1007/978-981-16-0267-2_8.

ABSTRACT

Infections by influenza virus constitute a major and recurrent threat for human health. Together with vaccines, antiviral drugs play a key role in the prevention and treatment of influenza virus infection and disease. Today, the number of antiviral molecules approved for the treatment of influenza is relatively limited, and their use is threatened by the emergence of viral strains with resistance mutations. There is therefore a real need to expand the prophylactic and therapeutic arsenal. This chapter summarizes the state of the art in drug discovery and development for the treatment of influenza virus infections, with a focus on both virus-targeting and host cell-targeting strategies. Novel antiviral strategies targeting other viral proteins or targeting the host cell, some of which are based on drug repurposing, may be used in combination to strengthen our therapeutic arsenal against this major pathogen.

PMID:34258742 | DOI:10.1007/978-981-16-0267-2_8

iScience. 2021 Jun 12;24(7):102722. doi: 10.1016/j.isci.2021.102722. eCollection 2021 Jul 23.

ABSTRACT

Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high heterogeneity. Stratification of ccRCC is important since distinct subtypes differ in prognosis and treatment. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Further, we developed a set of biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets. We identified four drug targets, including SOAT1, CRLS1, and ACACB, essential in all the three subtypes and GPD2, exclusively essential to subtype 1. Finally, we repositioned mitotane, an FDA-approved SOAT1 inhibitor, to treat ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth based on in vitro experiments.

PMID:34258555 | PMC:PMC8253978 | DOI:10.1016/j.isci.2021.102722

Nanomedicine (Lond). 2021 Jul 14. doi: 10.2217/nnm-2021-0130. Online ahead of print.

ABSTRACT

Despite the high incidence of breast cancer, there are few pharmacological prevention strategies for the high-risk population and those that are available have low adherence. Strategies that deliver drugs directly to the breasts may increase drug local concentrations, improving efficacy, safety and acceptance. The skin of the breast has been proposed as an administration route for local transdermal therapy, which may improve drug levels in the mammary tissue, due to both deep local penetration and percutaneous absorption. In this review, we discuss the application of nanotechnology-based strategies for the delivery of well established and new agents as well as drug repurposing using the topical transdermal route to improve the outcomes of preventive therapy for breast cancer.

PMID:34256574 | DOI:10.2217/nnm-2021-0130

Comput Biol Med. 2021 Jul 6;135:104634. doi: 10.1016/j.compbiomed.2021.104634. Online ahead of print.

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused worldwide pandemic and is responsible for millions of worldwide deaths due to -a respiratory disease known as COVID-19. In the search for a cure of COVID-19, drug repurposing is a fast and cost-effective approach to identify anti-COVID-19 drugs from existing drugs. The receptor binding domain (RBD) of the SARS-CoV-2 spike protein has been a main target for drug designs to block spike protein binding to ACE2 proteins. In this study, we probed the conformational plasticity of the RBD using long molecular dynamics (MD) simulations, from which, representative conformations were identified using clustering analysis. Three simulated conformations and the original crystal structure were used to screen FDA approved drugs (2466 drugs) against the predicted binding site at the ACE2-RBD interface, leading to 18 drugs with top docking scores. Notably, 16 out of the 18 drugs were obtained from the simulated conformations, while the crystal structure suggests poor binding. The binding stability of the 18 drugs were further investigated using MD simulations. Encouragingly, 6 drugs exhibited stable binding with RBD at the ACE2-RBD interface and 3 of them (gonadorelin, fondaparinux and atorvastatin) showed significantly enhanced binding after the MD simulations. Our study shows that flexibility modeling of SARS-CoV-2 RBD using MD simulation is of great help in identifying novel agents which might block the interaction between human ACE2 and the SARS-CoV-2 RBD for inhibiting the virus infection.

PMID:34256255 | DOI:10.1016/j.compbiomed.2021.104634

Recent Pat Anticancer Drug Discov. 2021 Jul 11. doi: 10.2174/1574892816666210712113739. Online ahead of print.

ABSTRACT

BACKGROUND: Malignant Mesothelioma (MM), an orphan but aggressive malignancy of the mesothelial membrane, is a fatal tumor. Global epidemic related to malignant pleural mesothelioma is on the rise, so there is a need to explore novel biomarkers and ingenious therapeutic approaches to stalk this silent killer.

OBJECTIVE: The main aim of the present review is to provide a consolidated overview of the recent active patents related to diagnosis and therapy in MM that will affect its future management.

METHOD: A search of existing literature was conducted from a PubMed database search. Recent patent information was fetched out from online accessible open-access databases. For related clinical trials, www.clinicaltrial.gov was searched.

RESULTS: Patent search data showed 72 active patents related to diagnosis and therapy in the field of MM, which we classified into eight broad categories. Of these, a maximum of 17 patents was attributed to immunotherapy, and 13 each were attributed to "Drug Repositioning" and "Biological / synthetic" based candidates. The remaining 17 patents were distributed amongst virotherapy and various miscellaneous categories. A relatively low number of patents accounts for gene signature (7), epigenetics (3), and microRNA (2) based diagnosis and therapy. Furthermore, our clinical trial-based investigation revealed the futuristic impact of listed patents in MM patient management.

CONCLUSION: This review article has provided an overview of patent-based advancement in MM, which might become the apex in clinical settings in the future. Interestingly, immunotherapy and "drug repositioning" based therapy seems to be the front-runners in the race to provide relief.

PMID:34254929 | DOI:10.2174/1574892816666210712113739

Curr Stem Cell Res Ther. 2021 Jul 12. doi: 10.2174/1574888X16666210712213102. Online ahead of print.

ABSTRACT

Nanomachines hold promise for the next generation of emerging technology; however, nanomachines are not a new concept, viruses, nature's nanomachines, have already existed for thousands of years. In 2019, the whole world has had to come together to confront a life-threatening nanomachine named "SARS-CoV-2", which causes COVID-19 illness. SARS-CoV-2, a smart nanomachine, attaches itself onto the ACE2 and CD147 receptors present on the cell surfaces of the lungs, kidneys, heart, brain, intestines, and testes, etc. and triggers pathogenesis. Cell entry triggers a cascade of inflammatory responses resulting in tissue damage, with the worst affected cases leading to death. SARS-CoV-2 influences several receptors and signalling pathways; therefore, finding a biomaterial that caps these signalling pathways and ligand sites is of interest. This research aimed to compare the similarities and differences between COVID-19 and its elderly sisters', MERS and SARS. Furthermore, we glanced at emerging therapeutics that carry potential in eliminating SARS-CoV-2, and the tissue damage it causes. Simple prophylactic and therapeutic strategies for the treatment of COVID-19 infection have been put forward.

PMID:34254928 | DOI:10.2174/1574888X16666210712213102

J Biomol Struct Dyn. 2021 Jul 13:1-14. doi: 10.1080/07391102.2021.1946715. Online ahead of print.

ABSTRACT

The main objective of this study is to find out the anti-SARS-CoV-2 potential of emetine by using molecular docking and dynamic simulation approaches. Interestingly, molecular docking studies suggest that Emetine showed significant binding affinity toward Nsp15 (-10.8 kcal/mol) followed by Nsp12 (-9.5 kcal/mol), RNA-dependent RNA polymerase, RdRp (-9.5 kcal/mol), Nsp16 (-9.4 kcal/mol), Nsp10 (-9.2 kcal/mol), Papain-like protein (-9.0 kcal/mol), Nsp13 (-9.0 kcal/mol), Nsp14 (-8.9 kcal/mol) and Spike Protein Receptor Domain (-8.8 kcal/mol) and chymotrypsin-like protease, 3CLpro (-8.5 kcal/mol), respectively, which are essential for viral infection and replication. In addition, molecular dynamic simulation (MD) was also performed for 140 ns to explore the stability behavior of the main targets and inhibitor complexes as well as the binding mechanics of the ligand to the target proteins. The obtained MD results followed by absolute binding energy calculation confirm that the binding of emetine at the level of the various receptors is more stable. The complex EmetineNSP15, mechanistically was stabilized as follows: Emetine first binds to the monomer, after, binds to the second inducing the formation of a dimer which in turn leading to the formation of complex that simulation stabilizes it at a value less than 5 Å. Overall, supported by the powerful and good pharmacokinetic data of Emetine, our findings with clinical trials may be helpful to confirm that Emetine could be promoted in the prevention and eradication of COVID-19 by reducing the severity in the infected persons and therefore can open possible new strategies for drug repositioning. Communicated by Ramaswamy H. Sarma.

PMID:34254564 | DOI:10.1080/07391102.2021.1946715

Eur Heart J. 2021 Jul 13:ehab427. doi: 10.1093/eurheartj/ehab427. Online ahead of print.

NO ABSTRACT

PMID:34254122 | DOI:10.1093/eurheartj/ehab427

J Pharmacol Exp Ther. 2021 Jul 12:JPET-AR-2021-000619. doi: 10.1124/jpet.121.000619. Online ahead of print.

ABSTRACT

In the wake of the COVID-19 pandemic, drug repurposing has been highlighted for rapid introduction of therapeutics. Proposed drugs with activity against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential targets for the organic cation (OC) secretory transporters of kidney and liver, i.e., the basolateral Organic Cation Transporters, OCT1 and OCT2; and the apical Multidrug And Toxin Extruders, MATE1 and MATE2-K. We selected several compounds proposed to have in vitro activity against SARS-CoV-2 (chloroquine, hydroxychloroquine, quinacrine, tilorone, pyronaridine, cetylpyridinium and miramistin), to test their interaction with OCT and MATE transporters. We used Bayesian Machine learning models to generate predictions for each molecule with each transporter and also experimentally determined IC50 values for each compound against labelled substrate transport into CHO cells that stably expressed OCT2, MATE1 or MATE2-K using three structurally distinct substrates (atenolol, metformin and 1-methyl-4-phenylpyridinium (MPP)) to assess the impact of substrate structure on inhibitory efficacy. For the OCTs substrate identity influenced IC50 values, though the effect was larger and more systematic for OCT2. In contrast, inhibition of MATE1-mediated transport was largely insensitive to substrate identity. Unlike MATE1, inhibition of MATE2-K was influenced, albeit modestly, by substrate identity. Cu,max/IC50 ratios were used to identify potential clinical DDI recommendations; all the compounds interacted with the OCT/MATE secretory pathway, most with sufficient avidity to represent potential DDI issues for secretion of cationic drugs. This should be considered when proposing cationic agents as repurposed antivirals. Significance Statement Drugs proposed as potential COVID-19 therapeutics based on in vitro activity data against SARS-CoV-2 include compounds with positive charges at physiological pH, making them potential interactors with the OCT/MATE renal secretory pathway. We tested seven such molecules as inhibitors of OCT1/2 and MATE1/2-K. All the compounds blocked transport activity regardless of substrate used to monitor activity. Suggesting that plasma concentrations achieved by normal clinical application of the test agents could be expected to influence the pharmacokinetics of selected cationic drugs.

PMID:34253645 | DOI:10.1124/jpet.121.000619