Cationic Compounds with SARS-CoV-2 Antiviral Activity and Their Interaction with Organic Cation Transporter/Multidrug and Toxin Extruder Secretory Transporters

Martinez-Guerrero, Lucy Jazmin; Zhang, Xiaohong; Zorn, Kimberley M.; Ekins, Sean; Wright, Stephen H.

doi:10.1124/jpet.121.000619

Cited by 8 publications

(16 citation statements)

References 57 publications

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“…The positive control included 10 μM of rifampicin. As we have seen substrate-dependent differences in Organic Cation Transporter inhibition previously, 73 we also tested two compounds, pyronaridine and tilorone, in both assays to assess the compatibility between the fluorescent (Eurofins) and radioactive OATP1B1 uptake assays (Wright lab) with the resulting comparisons shown in Figure S2A.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Machine Learning Models Identify New Inhibitors for Human OATP1B1

et al. 2022

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The uptake transporter OATP1B1 (SLC01B1) is largely localized to the sinusoidal membrane of hepatocytes and is a known victim of unwanted drug–drug interactions. Computational models are useful for identifying potential substrates and/or inhibitors of clinically relevant transporters. Our goal was to generate OATP1B1 in vitro inhibition data for [3H] estrone-3-sulfate (E3S) transport in CHO cells and use it to build machine learning models to facilitate a comparison of seven different classification models (Deep learning, Adaboosted decision trees, Bernoulli naïve bayes, k-nearest neighbors (knn), random forest, support vector classifier (SVC), logistic regression (lreg), and XGBoost (xgb)] using ECFP6 fingerprints to perform 5-fold, nested cross validation. In addition, we compared models using 3D pharmacophores, simple chemical descriptors alone or plus ECFP6, as well as ECFP4 and ECFP8 fingerprints. Several machine learning algorithms (SVC, lreg, xgb, and knn) had excellent nested cross validation statistics, particularly for accuracy, AUC, and specificity. An external test set containing 207 unique compounds not in the training set demonstrated that at every threshold SVC outperformed the other algorithms based on a rank normalized score. A prospective validation test set was chosen using prediction scores from the SVC models with ECFP fingerprints and were tested in vitro with 15 of 19 compounds (84% accuracy) predicted as active (≥20% inhibition) showed inhibition. Of these compounds, six (abamectin, asiaticoside, berbamine, doramectin, mobocertinib, and umbralisib) appear to be novel inhibitors of OATP1B1 not previously reported. These validated machine learning models can now be used to make predictions for drug–drug interactions for human OATP1B1 alongside other machine learning models for important drug transporters in our MegaTrans software.

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Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Machine Learning Models Identify New Inhibitors for Human OATP1B1

et al. 2022

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“…CADs are potentially of interest for other reasons, such as their potential for interfering with human transporters which could have potential undesirable effects. Several cationic compounds with SARS-CoV-2 antiviral activity were found to interact with OCT and MATE transporters in vitro, 45 and in some cases, this was influenced by the substrate used (e.g., for OCT1 and 2 but not for MATE1). Chloroquine, hydroxychloroquine, and quinacrine possessed IC 50 values between 1 and 10 μM for all these transporters.…”

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confidence: 99%

“…Several of the drugs tested had C unbound max /IC 50 values that would predict potential drug-transporter interactions in vivo. 45 It is unlikely that these would impact SARS-CoV-2 viral entry; however, it should also be pointed out that some transporters can be leveraged by viruses for entry, such as the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP). 46 We can also target transporters in order to reach viral sanctuary sites such as the testes, for example, using human equilibrative nucleoside transporters (ENT) whose structure-inhibitor and structure-substrate relationships we are just beginning to elucidate.…”

mentioning

confidence: 99%

“…Chloroquine, hydroxychloroquine, and quinacrine possessed IC 50 values between 1 and 10 μM for all these transporters. Several of the drugs tested had C unbound max /IC 50 values that would predict potential drug-transporter interactions in vivo . It is unlikely that these would impact SARS-CoV-2 viral entry; however, it should also be pointed out that some transporters can be leveraged by viruses for entry, such as the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP) .…”

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Defending Antiviral Cationic Amphiphilic Drugs That May Cause Drug-Induced Phospholipidosis

Lane

Ekins

2021

J. Chem. Inf. Model.

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A recent publication in Science has proposed that cationic amphiphilic drugs repurposed for COVID-19 typically use phosholipidosis as their antiviral mechanism of action in cells but will have no in vivo efficacy. On the contrary, our viewpoint, supported by additional experimental data for similar cationic amphiphilic drugs, indicates that many of these molecules have both in vitro and in vivo efficacy with no reported phospholipidosis, and therefore, this class of compounds should not be avoided but further explored, as we continue the search for broad spectrum antivirals.

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“…CADs are also of interest because of potential for interfering with human drug transporters. Cationic compounds with SARS-CoV-2 antiviral activity (chloroquine, hydroxychloroquine and quinacrine) inhibited OCT and MATE transporters in vitro (Martinez-Guerrero et al, 2021). An independent study has also evaluated 25 drugs used in COVID-19 clinical trials to assess the potential for drug-drug interactions (Yee et al, 2021).…”

Section: Drug Transportersmentioning

confidence: 99%

The Need for Speed and Efficiency: A Brief Review of Small Molecule Antivirals for COVID-19

Puhl

Lane

Urbina

et al. 2022

Front. Drug. Discov.

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While we currently have multiple highly effective vaccines approved for use against SARS-CoV-2 in the USA and other countries, there are far fewer small molecule antivirals approved to date. The emergence of the latest SARS-CoV-2 variant, Omicron which is heavily mutated in the spike protein, is also raising concerns about the effectiveness of these current vaccines and increasing the call for more therapeutic options. At the time of writing only remdesivir is approved by the FDA while molnupiravir (already approved in the United Kingdom) and Paxlovid (PF-07321332) have emergency use authorizations from the FDA. Repurposed molecules, such as dexamethasone and baricitinib, have been authorized for emergency use in some countries and are used in combination with remdesivir. After 2 years we are only now starting to see the progression of further molecules through animal models to assess their efficacy before clinical trials. As datasets accumulate from both in vitro and in vivo animal efficacy models, this may allow us to understand the physicochemical properties necessary for antiviral activity and enable the search for additional antivirals. We now summarize 25 small molecule drugs that are either approved, in the process of approval or in the pipeline for COVID which have both in vitro and in vivo data. We demonstrate that these drugs are structurally diverse and cover a wide chemistry space. This information may aid our understanding of what it takes to be a promising treatment for COVID-19 and propose how to discover antivirals faster and more efficiently for the next pandemic.

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Cationic Compounds with SARS-CoV-2 Antiviral Activity and Their Interaction with Organic Cation Transporter/Multidrug and Toxin Extruder Secretory Transporters

Cited by 8 publications

References 57 publications

Machine Learning Models Identify New Inhibitors for Human OATP1B1

Machine Learning Models Identify New Inhibitors for Human OATP1B1

Defending Antiviral Cationic Amphiphilic Drugs That May Cause Drug-Induced Phospholipidosis

The Need for Speed and Efficiency: A Brief Review of Small Molecule Antivirals for COVID-19

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