Didanosine

McLaren, Colin; Datema, Roelf; Knupp, Catherine A.; Buroker, R. A.

doi:10.1177/095632029100200601

Cited by 26 publications

(12 citation statements)

References 50 publications

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“…Thus, compared to dogs, monkeys would be more likely to achieve the exposure to EMV needed for adequate safety assessment. Dose-limiting neurological toxicities have been encountered with the clinical use of nucleoside analogs, most notably dideoxycytidine (6) and dideoxyinosine (24). Monkeys are a good model for studying potential effects of new antiviral drugs on the peripheral nervous system because noninvasive techniques to measure the conduction velocity in peripheral nerves exist.…”

Section: Discussionmentioning

confidence: 99%

Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1

Szczech

Furman

Painter

et al. 2000

Antimicrob Agents Chemother

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Emivirine (EMV), formerly known as MKC-442, is 6-benzyl-1-(ethoxymethyl)-5-isopropyl-uracil, a novel nonnucleoside reverse transcriptase inhibitor that displays potent and selective anti-human immunodeficiency virus type 1 (HIV-1) activity in vivo. EMV showed little or no toxicity towards human mitochondria or human bone marrow progenitor cells. Pharmacokinetics were linear for both rats and monkeys, and oral absorption was 68% in rats. Whole-body autoradiography showed widespread distribution in tissue 30 min after rats were given an oral dose of [ 14 C]EMV at 10 mg/kg of body weight. In rats given an oral dose of 250 mg/kg, there were equal levels of EMV in the plasma and the brain. In vitro experiments using liver microsomes demonstrated that the metabolism of EMV by human microsomes is approximately a third of that encountered with rat and monkey microsomes. In 1-month, 3-month, and chronic toxicology experiments (6 months with rats and 1 year with cynomolgus monkeys), toxicity was limited to readily reversible effects on the kidney consisting of vacuolation of kidney tubular epithelial cells and mild increases in blood urea nitrogen. Liver weights increased at the higher doses in rats and monkeys and were attributed to the induction of drug-metabolizing enzymes. EMV tested negative for genotoxic activity, and except for decreased feed consumption at the high dose (160 mg/kg/day), with resultant decreases in maternal and fetal body weights, EMV produced no adverse effects in a complete range of reproductive toxicology experiments performed on rats and rabbits. These results support the clinical development of EMV as a treatment for HIV-1 infection in adult and pediatric patient populations.

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Section: Discussionmentioning

confidence: 99%

Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1

Szczech

Furman

Painter

et al. 2000

Antimicrob Agents Chemother

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“…Didanosine is also a medication used to slow the progress of HIV/AIDS and is a nucleoside analogue of adenosine. There are several common adverse effects associated with this medication including diarrhea, vomiting, and peripheral neuropathy 127 . Fenoterol has already been recommended to reduce severe pulmonary symptoms of COVID-19 patients 128 .…”

Section: Resultsmentioning

confidence: 99%

<strong>Revealing SARS-CoV-2 Functional Druggability Through Multi-Target Cadd Screening of Repurposable Drugs</strong>

Gupta¹,

Maciorowski²,

Mathur³

et al. 2020

Preprint

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The emergence of SARS/MERS drug resistant COVID-19 with high transmission and mortality has recently been declared a deadly pandemic causing economic chaos and significant health problems. Like all coronaviruses, SARS-CoV-2 is a large virus that has many druggable components within its proteome. In this study, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes within SARS-CoV-2. We shortlisted seven target proteins with enzymatic activities known to be essential at different stages of the virus life cycle. For virtual screening, the energy minimization of a crystal structure or modeled protein was carried out using Protein Preparation Wizard (Schrödinger LLC, 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are already approved by worldwide regulatory bodies including the FDA, using the ZINC database. Screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. A top lead from each target group was further subjected to molecular dynamics simulation (MDS) using the Desmond module to validate the efficacy of the screening pipeline. All of the simulated hit-target complexes were predicted to strongly interact and with highly stable binding. Thus, we have identified a number of approved and investigational drugs with high likelihood of inhibiting a variety of key SARS-CoV-2 proteins. Follow-up studies will continue to identify inhibitors suitable for combination therapy based on drug-drug synergy to thwart resistance. In addition, the screening hits that we have identified provide excellent probes for understanding the binding properties of the active sites of all seven targets, further enabling us to derive consensus molecules through computer-aided drug design (CADD). While infections are expanding at a rampant pace, it must be recognized that resistance will grow commensurately through either genetic shift and/or genetic drift to all small molecule drugs identified. Vaccines should provide a more permanent solution through prevention, but resistivity is still a possible scenario. Nevertheless, a persistent multi-target drug development program is essential to curb this ongoing pandemic and to keep reemergence in check.

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“…There are several common adverse effects associated with this medication including diarrhea, vomiting, and peripheral neuropathy 89 .…”

Section: Resultsmentioning

confidence: 99%

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

Gupta

Maciorowski

Zak

et al. 2020

Preprint

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The emergence of SARS/MERS drug-resistant SARS-CoV2 comes with higher rates of transmission and mortality. Like all coronaviruses, SARS-CoV-2 is a relatively large virus consisting of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs by identifying potential drugs that are predicted to effectively inhibit critical enzymes. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral multiplication cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2’-O-MT. For virtual screening, the energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard(Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs (n=5903) that are approved by worldwide regulatory bodies. The screening was performed against viral targets using three sequential docking modes (i.e. HTVS, SP, and XP). Our in-silico virtual screening identified ~290 potential drugs based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. Herein we report the evaluation of in-vitro efficacy of selected hit drug molecules on SARS-CoV-2 inhibition. Among eight molecules included in our evaluation, we found inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), as the potent inhibitor of SARS-CoV-2 in-vitro. Further, in-silico predicted target validation through enzymatic assays confirmed 3CLpro to be the target. Therefore, our data support advancing BIM IX for clinical evaluation as a potential treatment for COVID-19. This is the first study that has showcased the possibility of using bisindolylmaleimide IX to treat COVID-19 through this pipeline.

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Didanosine

Cited by 26 publications

References 50 publications

Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1

Safety Assessment, In Vitro and In Vivo, and Pharmacokinetics of Emivirine, a Potent and Selective Nonnucleoside Reverse Transcriptase Inhibitor of Human Immunodeficiency Virus Type 1

<strong>Revealing SARS-CoV-2 Functional Druggability Through Multi-Target Cadd Screening of Repurposable Drugs</strong>

Bisindolylmaleimide IX: A novel anti-SARS-CoV2 agent targeting viral main protease 3CLpro demonstrated by virtual screening and in vitro assays

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