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Rxivist combines biology preprints from bioRxiv and medRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 124,257 papers from 533,889 authors.

Most downloaded biology preprints, since beginning of last month

in category pharmacology and toxicology

1,007 results found. For more information, click each entry to expand.

1: Iota carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture
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Posted 21 Aug 2020

Iota carrageenan and xylitol inhibit SARS-CoV-2 in Vero cell culture
1,423 downloads bioRxiv pharmacology and toxicology

Julio Cesar Vega, Shruti Bansal, Colleen B Jonsson, Shannon L. Taylor, Juan M Figueroa, Andrea V. Dugour, Carlos Palacios

COVID-19 (coronavirus disease 2019) is a pandemic caused by SARS-CoV-2 (severe acute respiratory syndrome-coronavirus 2) infection affecting millions of persons around the world. There is an urgent unmet need to provide an easy-to-produce, affordable medicine to prevent transmission and provide early treatment for this disease. The nasal cavity and the rhinopharynx are the sites of initial replication of SARS-CoV-2. Therefore, a nasal spray may be a suitable dosage form for this purpose. The main objective of our study was to test the antiviral action of three candidate nasal spray formulations against SARS-CoV-2. We have found that iota-carrageenan in concentrations as low as 6 mcg/ mL inhibits SARS-CoV-2 infection in Vero cell cultures. The concentrations found to be active in vitro against SARS-CoV-2 may be easily achieved by the application of nasal sprays already marketed in several countries. Xylitol at a concentration of 5 % m/V has proved to be viricidal on its own and the association with iota-carrageenan may be beneficial, as well. ### Competing Interest Statement The study has been funded by Amcyte Pharma Inc. (US) Juan Manuel Figueroa, Andrea Dugour and Carlos Palacios receive funding from Fundacion Pablo Cassara (Argentina) Julio Cesar Vega receives salary from Laboratorio Pablo Cassara and is inventor of a US patent application related to this manuscript.

2: Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model
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Posted 24 Oct 2020

Ivermectin repurposing for COVID-19 therapy: Safety and pharmacokinetic assessment of a novel nasal spray formulation in a pig model
879 downloads bioRxiv pharmacology and toxicology

Jorge Errecalde, Adrian Lifschitz, Graciela Vecchioli, Laura Ceballos, Francisco Errecalde, Mariana Ballent, Gustavo Marin, Martin Daniele, Esteban Turic, Eduardo Spitzer, Fernando Toneguzzo, Silvia Gold, Alejandro Krolewiecki, Luis Alvarez, Carlos Lanusse

High ivermectin (IVM) concentrations suppress in vitro SARS-CoV-2 replication. Nasal IVM spray (NIVM spray) administration may contribute to attaining high drug concentrations in nasopharyngeal (NP) tissue, a primary site of virus entrance/replication. The safety and pharmacokinetic performance of a new NIVM spray formulation in a piglet model were assessed. Crossbred piglets (10/12 kg) were treated with either one or two (12 h apart) doses of N IVM spray (2 mg, 1 puff/nostril) or orally (0.2 mg/kg). The overall safety of NIVM-spray was assessed (clinical, haematological, serum biochemical determinations), and histopathology evaluation of the application site tissues performed. The IVM concentration profiles measured in plasma and respiratory tract tissues (nasopharynx and lungs) after the nasal spray treatment (one and two applications) were compared with those achieved after the oral administration. Animals tolerated well the novel NIVM spray formulation. No local/systemic adverse events were observed. After nasal administration, the highest IVM concentrations were measured in NP and lung tissues. Significant increases in IVM concentration profiles in both NPtissue and lungs were observed after the 2 dose nasal administrations. The nasal/oral IVM concentration ratios in NP and lung tissues (at 6 h postdose) markedely increased by repeating the spray application. The fast attainment of high and persistent IVM concentrations in NP tissue is the main advantage of the nasal over the oral route. These original results are encouraging to support the undertaking of further clinical trials to evaluate the safety/efficacy of the nasal IVM spray application in the treatment and/or prevention of COVID-19. ### Competing Interest Statement The authors have declared no competing interest.

3: Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19
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Posted 13 Sep 2020

Discovery of a Novel Inhibitor of Coronavirus 3CL Protease as a Clinical Candidate for the Potential Treatment of COVID-19
512 downloads bioRxiv pharmacology and toxicology

Britton Boras, Rhys M. Jones, Brandon J. Anson, Dan Arenson, Lisa Aschenbrenner, Malina A. Bakowski, Nathan Beutler, Joseph Binder, Emily Chen, Heather Eng, Jennifer Hammond, Robert Hoffman, Eugene P. Kadar, Rob Kania, Emi Kimoto, Melanie G. Kirkpatrick, Lorraine Lanyon, Emma K. Lendy, Jonathan R. Lillis, Suman A. Luthra, Chunlong Ma, Stephen Noell, R. Scott Obach, Matthew N. O’ Brien, Rebecca O’Connor, Kevin Ogilvie, Dafydd Owen, Martin Pettersson, Matthew R Reese, Thomas F Rogers, Michelle I. Rossulek, Jean G. Sathish, Claire Steppan, Martyn Ticehurst, Lawrence W. Updyke, Yuao Zhu, Jun Wang, Arnab K. Chatterjee, Andrew D. Mesecar, Annaliesa S. Anderson, Charlotte Allerton

COVID-19 caused by the SARS-CoV-2 virus has become a global pandemic. 3CL protease is a virally encoded protein that is essential to the viral life cycle across a broad spectrum of coronaviruses with no close human analogs. The designed phosphate prodrug PF-07304814 is metabolized to PF-00835321 which is a potent inhibitor in vitro of the coronavirus family 3CL pro, with selectivity over human host protease targets. Furthermore, PF-00835231 exhibits potent in vitro antiviral activity against SARS-CoV-2 as a single agent and it is additive/synergistic in combination with remdesivir. We present the ADME, safety, and in vitro antiviral activity data to warrant clinical evaluation. One Sentence Summary The phosphate prodrug PF-07304814 is disclosed as an investigational novel intravenous small molecule 3CL protease inhibitor for COVID-19. ### Competing Interest Statement A.D.M has a sponsored program contract with Pfizer to test compounds for inhibition of coronavirus proteases. JW has a sponsored research agreement with Pfizer to test compounds for inhibition of coronavirus proteases.

4: LSD impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision making
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Posted 28 Jan 2019

LSD impairs working memory, executive functions, and cognitive flexibility, but not risk-based decision making
450 downloads bioRxiv pharmacology and toxicology

Thomas Pokorny, Patricia Duerler, Erich Seifritz, Franz X. Vollenweider, Katrin H. Preller

Psychiatric and neurodegenerative illnesses are characterized by cognitive impairments, in particular deficits in working memory, decision making, and executive functions including cognitive flexibility. However, the neuropharmacology of these cognitive functions is poorly understood. The serotonin (5-HT) 2A receptor might be a promising candidate for the modulation of cognitive processes. However, pharmacological studies investigating the role of this receptor system in humans are rare. Recent evidence demonstrates that the effects of Lysergic acid diethylamide (LSD) are mediated via agonistic action at the 5-HT2A receptor. Yet, the effects of LSD on specific cognitive domains using standardized neuropsychological test have not been studied. Therefore, we examined the acute effects of LSD (100 micrograms) alone and in combination with the 5-HT2A antagonist ketanserin (40mg) on cognition, employing a double-blind, randomized, placebo-controlled, within-subject design in 25 healthy participants. Executive functions, cognitive flexibility, spatial working memory, and risk-based decision-making were examined by the Intra/Extra-Dimensional shift task (IED), Spatial Working Memory task (SWM), and Cambridge Gambling Task (CGT) of the Cambridge Neuropsychological Test Automated Battery. Compared to placebo, LSD significantly impaired executive functions, cognitive flexibility, and working memory on the IED and SWM, but did not influence quality of decision-making and risk-taking on the CGT. Pretreatment with the 5-HT2A antagonist ketanserin normalized all LSD-induced cognitive deficits. The present findings highlight the role of the 5-HT2A receptor system in executive functions and working memory and suggest that specific 5-HT2A antagonists may be relevant for improving cognitive dysfunctions in psychiatric disorders.

5: Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine and Pyronaridine: In vitro Activity Against SARS-CoV-2 and Potential Mechanisms
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Posted 02 Dec 2020

Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine and Pyronaridine: In vitro Activity Against SARS-CoV-2 and Potential Mechanisms
346 downloads bioRxiv pharmacology and toxicology

Ana C Puhl, Ethan J Fritch, Thomas R Lane, Longping V. Tse, Boyd Yount, Carol Q Sacramento, Tatyana A Tavella, Fabio T. M. Costa, Stuart Weston, James Logue, Matthew Frieman, Lakshmanane Premkumar, Kenneth H. Pearce, Brett L Hurst, Carolina H Andrade, James A Levi, Nicole J Johnson, Samantha C Kisthardt, Frank Scholle, Thiago ML Souza, Nathanial J Moorman, Ralph S. Baric, Peter Madrid, Sean Ekins

SARS-CoV-2 is a newly identified virus that has resulted in over 1.3 M deaths globally and over 59 M cases globally to date. Small molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola virus and demonstrated activity against SARS-CoV-2 in vivo. Most notably the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small molecule drugs that are active against Ebola virus would seem a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg virus in vitro in HeLa cells and of mouse adapted Ebola virus in mouse in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7 and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We have also tested them in a pseudovirus assay and used microscale thermophoresis to test the binding of these molecules to the spike protein. They bind to spike RBD protein with Kd values of 339 nM and 647 nM, respectively. Human Cmax for pyronaridine and quinacrine is greater than the IC50 hence justifying in vivo evaluation. We also provide novel insights into their mechanism which is likely lysosomotropic.

6: First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug.
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Posted 04 Dec 2020

First-described recently discovered non-toxic vegetal-derived furocoumarin preclinical efficacy against SARS-CoV-2: a promising antiviral herbal drug.
329 downloads bioRxiv pharmacology and toxicology

Ivan Jose Galindo-Cardiel, Adriana Toledo Nunez, Maria Celaya Fernandez, Ariel Ramirez Labrada, Iratxe Uranga-Murillo, Maykel Arias Cabrero, Julian Pardo, Ezio Panzeri

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiology of coronavirus disease 2019 (COVID19) pandemic. ICEP4 purified compound (ICEP4) is a recently discovered furocoumarin-related purified compound coming from roots and seeds of Angelica archangelica (herbal drug). ICEP4-related herbal preparations have been extensively used as active herbal ingredient in traditional medicine treatments in several European countries. Extraction method of patent pending ICEP4 (patent application no. GB2017123.7) has showed previously strong manufacturing robustness, long-lasting stability, and repeated chemical consistency. Here we show that ICEP4 presents a significant in vitro cytoprotective effect in highly virulent-SARS-CoV-2 challenged Vero E6 cellular cultures by using 34.5 and 69 {micro}M doses. No dose related ICEP4 toxicity was seen on Vero E6 cells, M0 macrophages, B, CD4+ T and CD8+ T lymphocytes, Natural Killer (NK) and Natural Killer T (NKT) cells. No dose related ICEP4 inflammatory response was observed in M0 macrophages quantified by IL6 and TNF release in cell supernatant. No survival rate decrease was observed neither on 24-hour acute nor 21-days chronic in vivo toxicity studies performed in C. elegans. Therefore, ICEP4 toxicological profile has demonstrated marked differences compared to others vegetal furocoumarins. Successful ICEP4 doses against SARS-CoV-2-challenged cells are within the maximum threshold of toxicity concern (TTC) of furocoumarins as herbal preparation, stated by European Medicines Agency (EMA). Characteristic ICEP4 chemical compounding and its safe TTC let us to assume that an antiviral first-observed natural compound has been discovered. Potential druggability of a new synthetic ICEP4-related compound remains to be elucidated. However, well-established historical use of ICEP4-related compounds as herbal preparations may point towards an already-safe widely extended remedy, which may be ready-to-go for large-scale clinical trials under EMA emergency regulatory pathway. To the best of authors knowledge, ICEP4-related herbal drug can be postulated as a promising therapeutic treatment for COVID19.

7: Ribavirin shows antiviral activity against SARS-CoV-2 and downregulates the activity of TMPRSS2 and the expression of ACE2 in vitro
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Posted 05 Dec 2020

Ribavirin shows antiviral activity against SARS-CoV-2 and downregulates the activity of TMPRSS2 and the expression of ACE2 in vitro
318 downloads bioRxiv pharmacology and toxicology

Mehmet Altay Unal, Ceylan Verda Bitirim, Gokce Yagmur Summak, Sidar Bereketoglu, Inci Cevher Zeytin, Omur Besbinar, Cansu Gurcan, Dunya Aydos, Ezgi Goksoy, Ebru Kocakaya, Zeynep Eran, Merve Murat, Nil Demir, Julia Somers, Emek Demir, Hasan Nazir, Sibel Aysil Ozkan, Aykut Ozkul, Alpay Azap, Acelya Yilmazer, Kamil Can Akcali

Ribavirin is a guanosine analog and has a broad-spectrum antiviral activity against RNA viruses. Based on this, we aimed to show the anti-SARS-CoV-2 activity of this drug molecule via in vitro, in silico and molecular techniques. Ribavirin showed antiviral activity in Vero E6 cells following SARS-CoV-2 infection. In silico analysis suggested that Ribarivin has a broad-spectrum impact on Vero E6 cells. According to the detailed molecular techniques, Ribavirin was shown to decrease TMPRSS2 expression both at mRNA and protein level 48 hours after treatment. The suppressive effect of Ribavirin in ACE2 protein expression was shown to be dependent on cell types. Finally, proteolytic activity assays showed that Ribavirin also showed an inhibitory effect on TMPRSS2 enzyme. As a conclusion, Ribavirin is a potential antiviral drug for the treatment against SARS-CoV-2, and it interferes with the effect of TMPRSS2 and ACE2 expression.

8: Effective buprenorphine use and tapering strategies: Endorsements and insights by people in recovery from opioid use disorder on a Reddit forum
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Posted 11 Dec 2019

Effective buprenorphine use and tapering strategies: Endorsements and insights by people in recovery from opioid use disorder on a Reddit forum
311 downloads bioRxiv pharmacology and toxicology

Rachel L Graves, Abeed Sarker, Mohammed Ali Al-Garadi, Yuan-chi Yang, Jennifer S Love, Karen O'Connor, Graciela Gonzalez-Hernandez, Jeanmarie Perrone

Opioid use disorder (OUD) is a public health emergency in the United States. Over 47,000 overdose-related deaths in 2017 involved opioids. Medication-assisted treatment (MAT), in particular, buprenorphine and buprenorphine combination products such as Suboxone®, is the most effective, evidence-based treatment for OUD. However, there are a limited number of conclusive scientific studies that provide guidance to medical professionals about strategies for using buprenorphine to achieve stable recovery. In this study, we used data-driven natural language processing methods to mine a total of 16,146 posts about buprenorphine from 1933 unique users on the anonymous social network Reddit. Analysis of a sample of these posts showed that 74% of the posts described users’ personal experiences and that the top three topics included advice on using Suboxone® (55.0%), Suboxone® dosage information (35.5%) and information about Suboxone® tapering (32.0%). Based on two models, one that incorporated ‘upvoting’ by other members and one that did not, we found that Reddit users reported more successful recovery with longer tapering schedules, particularly from 2.0 mg to 0.0 mg (median: 93 days; mean: 95 days), as compared to shorter tapering schedules investigated in past clinical trials. Diarrhea, insomnia, restlessness, and fatigue were commonly reported adverse events. Physical exercise, clonidine, and Imodium® were frequently reported to help during the recovery process. Due to the difficulties of conducting longer-term clinical trials involving patients with OUD, clinicians should consider other information sources including peer discussions from the abundant, real-time information available on Reddit. Significance Statement Opioid use disorder (OUD) is a national crisis in the United States and buprenorphine is one of the most effective evidence-based treatments. However, few studies have explored successful strategies for using and tapering buprenorphine to achieve stable recovery, particularly due to the difficulties of conducting long-term studies involving patients with OUD. In this study, we show that discussions on the anonymous social network Reddit may be leveraged, via automatic text mining methods, to discover successful buprenorphine use and tapering strategies. We discovered that longer tapering schedules, compared to those investigated in past clinical trials, may lead to (self-reported) sustained recovery. Furthermore, Reddit posts also provide key information regarding buprenorphine withdrawal, cravings, adjunct medications for withdrawal symptoms and relapse prevention strategies.

9: Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations
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Posted 09 Dec 2018

Toxicity of JUUL Fluids and Aerosols Correlates Strongly with Nicotine and Some Flavor Chemical Concentrations
258 downloads bioRxiv pharmacology and toxicology

Esther E. Omaiye, Kevin J McWhirter, Wentai Luo, James F Pankow, Prue Talbot

While JUUL electronic cigarettes (ECs) have captured the majority of the EC market with a large fraction of their sales going to adolescents, little is known about their cytotoxicity and potential effects on health. The purpose of this study was to determine flavor chemical and nicotine concentrations in the eight currently marketed pre-filled JUUL EC cartridges (pods) and to evaluate the cytotoxicity of the different variants (e.g., Cool Mint and Creme Brulee) using in vitro assays. Nicotine and flavor chemicals were analyzed using gas chromatography/mass spectrometry in pod fluid before and after vaping and in the corresponding aerosols. 59 flavor chemicals were identified in JUUL pod fluids, and three were >1 mg/mL. Duplicate pods were similar in flavor chemical composition and concentration. Nicotine concentrations (average 60.9 mg/mL) were significantly higher than any EC products we have analyzed previously. Transfer efficiency of individual flavor chemicals that were >1mg/mL and nicotine from the pod fluid into aerosols was generally 35 - 80%. All pod fluids were cytotoxic at a 1:10 dilution (10%) in the MTT and neutral red uptake assays when tested with BEAS-2B lung epithelial cells. Most aerosols were cytotoxic in these assays at concentrations >1%. The cytotoxicity of aerosols was highly correlated with nicotine and ethyl maltol concentrations and moderately to weakly correlated with total flavor chemical concentration and menthol concentration. Our study demonstrates that: (1) some JUUL flavor pods have high concentrations of flavor chemicals that may make them attractive to youth, and (2) the concentrations of nicotine and some flavor chemicals (e.g. ethyl maltol) are high enough to be cytotoxic in acute in vitro assays, emphasizing the need to determine if JUUL products will lead to adverse health effects with chronic use.

10: Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters
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Posted 23 Nov 2020

Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters
258 downloads bioRxiv pharmacology and toxicology

Agnes Telbisz, Csilla Ambrus, Orsolya Mozner, Edit Szabo, Gyorgy Varady, Eva Bakos, Balazs Sarkadi, Csilla Ozvegy-Laczka

In the COVID-19 epidemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied together with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, here we examined the interactions of the repurposed drugs with the key human multidrug transporters, present in the major tissue barriers and strongly affecting pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine, the antihelmintic ivermectin, and the proposed antiviral compounds, ritonavir, lopinavir, favipiravir and remdesivir with the ABCB1/Pgp, ABCG2/BCRP and ABCC1/MRP1 exporters, as well as the OATP2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning for the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.

11: SARS-CoV-2 inhibition in human airway epithelial cells using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray
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Posted 10 Dec 2020

SARS-CoV-2 inhibition in human airway epithelial cells using a mucoadhesive, amphiphilic chitosan that may serve as an anti-viral nasal spray
246 downloads bioRxiv pharmacology and toxicology

Krzysztof Pyrc, Aleksandra Milewska, Emilia Baretto Duran, Pawel Botwina, Rui Lopes, Alejandro Arenas-Pinto, Moutaz Badr, Ryan Mellor, Tammy Kalber, Delmiro Fernandez-Reyes, Andreas G. Schatzlein, Ijeoma F. Uchegbu

There are currently no cures for coronavirus infections, making the prevention of infections the only course open at the present time. The COVID-19 pandemic has been difficult to prevent, as the infection is spread by respiratory droplets and thus effective, scalable and safe preventive interventions are urgently needed. We hypothesise that preventing viral entry into mammalian nasal epithelial cells may be one way to limit the spread of COVID-19. Here we show that N-palmitoyl-N-monomethyl-N,N-dimethyl-N,N,N-trimethyl-6-O-glycolchitosan (GCPQ), a positively charged polymer that has been through an extensive Good Laboratory Practice toxicology screen, is able to reduce the infectivity of SARS-CoV-2 in A549ACE2+ and Vero E6 cells with a log removal value of -3 to -4 at a concentration of 10 - 100 micrograms/mL (p < 0.05 compared to untreated controls) and to limit infectivity in human airway epithelial cells at a concentration of 500 micrograms/mL (p < 0.05 compared to untreated controls). GCPQ is currently being developed as a pharmaceutical excipient in nasal and ocular formulations. The electrostatic binding of GCPQ to the virus, preventing viral entry into the host cells, is the most likely mechanism of viral inhibition. Radiolabelled GCPQ studies in mice show that at a dose of 10 mg/kg, GCPQ has a long residence time in mouse nares, with 13.5% of the dose being present in the nares, 24 hours after nasal dosing. With a no observed adverse effect level of 18 mg/kg in rats following a 28 day repeat dose study, clinical testing of this polymer, as a COVID-19 prophylactic is warranted.

12: A small-molecule oral agonist of the human glucagon-like peptide-1 receptor
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Posted 30 Sep 2020

A small-molecule oral agonist of the human glucagon-like peptide-1 receptor
227 downloads bioRxiv pharmacology and toxicology

David A. Griffith, David J. Edmonds, Jean-Phillipe Fortin, Amit S. Kalgutkar, J. Brent Kuzmiski, Paula M. Loria, Aditi R. Saxena, Scott W. Bagley, Clare Buckeridge, John M. Curto, David R. Derksen, João M. Dias, Matthew C. Griffor, Seungil Han, V. Margaret Jackson, Margaret S. Landis, Daniel J. Lettiere, Chris Limberakis, Yuhang Liu, Alan M. Mathiowetz, David W. Piotrowski, David A. Price, Roger B. Ruggeri, David A. Tess

Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited by the requirement for injection. Here we describe the first effective, orally bioavailable small molecule GLP-1R agonists. A sensitized high-throughput screen identified a series of small molecule GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nM potency. These small molecule agonists increased insulin levels in primates but not rodents, which is explained by a cryo-EM structure that revealed a binding pocket requiring primate-specific tryptophan 33. Importantly, oral administration of agonist PF-06882961 to healthy humans produced dose-dependent declines in serum glucose ([NCT03309241][1]). This opens the door to a new era of oral small molecule therapies that target the well-validated GLP-1R pathway for metabolic health. One Sentence Summary PF-06882961 is an orally administered small molecule that activates the GLP-1 receptor to lower blood glucose in humans. ### Competing Interest Statement ASK, AMM, MCG, JMD, CB, CL, SWB, DJL, PML, DRD, JMC, JPF, YL, ARS, DAT, DWP, SH, RBR, MSL, and DAG are employees and stockholders of Pfizer Inc. DAP, DJE, JBK and VMJ are stockholders of Pfizer Inc. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03309241&atom=%2Fbiorxiv%2Fearly%2F2020%2F09%2F30%2F2020.09.29.319483.atom

13: Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro
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Posted 12 Apr 2020

Scutellaria baicalensis extract and baicalein inhibit replication of SARS-CoV-2 and its 3C-like protease in vitro
218 downloads bioRxiv pharmacology and toxicology

Hongbo Liu, Fei Ye, Qi Sun, Hao Liang, Chunmei Li, Roujian Lu, Baoying Huang, Wenjie Tan, Luhua Lai

COVID-19 has become a global pandemic that threatens millions of people worldwide. There is an urgent call for developing effective drugs against the virus (SARS-CoV-2) causing this disease. The main protease of SARS-CoV-2, 3C-like protease (3CLpro), is highly conserved across coronaviruses and is essential for the maturation process of viral polyprotein. Scutellariae radix (Huangqin in Chinese), the root of Scutellaria baicalensis has been widely used in traditional Chinese medicine to treat viral infection related symptoms. The extracts of S. baicalensis have exhibited broad spectrum antiviral activities. We studied the anti-SARS-CoV-2 activity of S. baicalensis and its ingredient compounds. We found that the ethanol extract of S. baicalensis inhibits SARS-CoV-2 3CLpro activity in vitro and the replication of SARS-CoV-2 in Vero cells with an EC50 of 0.74 μg/ml. Among the major components of S. baicalensis, baicalein strongly inhibits SARS-CoV-2 3CLpro activity with an IC50 of 0.39 μM. We further identified four baicalein analogue compounds from other herbs that inhibit SARS-CoV-2 3CLpro activity at microM concentration. Our study demonstrates that the extract of S. baicalensis has effective anti-SARS-CoV-2 activity and baicalein and analogue compounds are strong SARS-CoV-2 3CLpro inhibitors. ### Competing Interest Statement The authors have declared no competing interest.

14: Platycodin D prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection in vitro by hindering membrane fusion
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Posted 23 Dec 2020

Platycodin D prevents both lysosome- and TMPRSS2-driven SARS-CoV-2 infection in vitro by hindering membrane fusion
199 downloads bioRxiv pharmacology and toxicology

Tai Young Kim, Sangeun Jeon, Youngho Jang, Lizaveta Gotina, Joungha Won, Yeon Ha Ju, Sunpil Kim, Minwoo Wendy Jang, Woojin Won, Mingu Gordon Park, Ae Nim Pae, Sunkyu Han, Seungtaek Kim, C. Justin Lee

An ongoing pandemic of coronavirus disease 2019 (COVID-19) is now the greatest threat to the global public health. Herbal medicines and their derived natural products have drawn much attention to treat COVID-19, but there has been no natural product showing inhibitory activity against SARS-CoV-2 infection with detailed mechanism. Here, we show that platycodin D (PD), a triterpenoid saponin abundant in Platycodon grandiflorum (PG), a dietary and medicinal herb commonly used in East Asia, effectively blocks the two main SARS-CoV-2 infection-routes via lysosome- and transmembrane protease, serine 2 (TMPRSS2)-driven entry. Mechanistically, PD prevents host-entry of SARS-CoV-2 by redistributing membrane cholesterol to prevent membrane fusion, which can be reinstated by treatment with a PD-encapsulating agent. Furthermore, the inhibitory effects of PD are recapitulated by a pharmacological inhibition or gene-silencing of NPC1, which is mutated in Niemann-Pick type C (NPC) patients displaying disrupted membrane cholesterol. Finally, readily available local foods or herbal medicines containing PG root show the similar inhibitory effects against SARS-CoV-2 infection. Our study proposes that PD is a potent natural product for preventing or treating COVID-19 and that a brief disruption of membrane cholesterol can be a novel therapeutic approach against SARS-CoV-2 infection.

15: Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson's disease in vivo
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Posted 07 Dec 2020

Protective effects of saffron and its constituent crocetin to motor symptoms, short life span and rough-eyed phenotypes in the fly models of Parkinson's disease in vivo
194 downloads bioRxiv pharmacology and toxicology

Eiji Inoue, Takahiro Suzuki, Yasuharu Shimizu, Keiichi Sudo, Haruhisa Kawasaki, Norio Ishida

Parkinson's disease (PD) is a common neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the brain. a-Synuclein is an aggregation-prone neural protein that plays a role in the pathogenesis of PD. In our previous paper, we found that saffron; the stigma of Crocus sativus Linne (Iridaceae), and its constituents (crocin and crocetin) suppressed aggregation of a-synuclein and promoted the dissociation of a-synuclein fibrils in vitro. In this study, we investigated the effect of dietary saffron and its constituent, crocetin, in vivo on a fly PD model overexpressing several mutant a-synuclein in a tissue-specific manner. Saffron and crocetin significantly suppressed the decrease of climbing ability in the Drosophila overexpressing A30P (A30P fly PD model) or G51D (G51D fly PD model) mutated a-synuclein in neurons. Saffron and crocetin extended the life span in the G51D fly PD model. Saffron suppressed the rough-eyed phenotype and the dispersion of the size histogram of the ocular long axis in A30P fly PD model in eye. Saffron had a cytoprotective effect on a human neuronal cell line with a-synuclein fibrils. These data showed that saffron and its constituent crocetin have protective effects on the progression of PD disease in animals in vivo and suggest that saffron and crocetin can be used to treat PD.

16: Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein’s Receptor Binding Domain and Recombinant Human ACE2
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Posted 14 Sep 2020

Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein’s Receptor Binding Domain and Recombinant Human ACE2
191 downloads bioRxiv pharmacology and toxicology

Omonike A Olaleye, Manvir Kaur, Collins C. Onyenaka

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), enters the host cells through two main pathways, both involving key interactions between viral envelope-anchored spike glycoprotein of the novel coronavirus and the host receptor, angiotensin-converting enzyme 2 (ACE2). To date, SARS-CoV-2 has infected up to 26 million people worldwide; yet, there is no clinically approved drug or vaccine available. Therefore, a rapid and coordinated effort to re-purpose clinically approved drugs that prevent or disrupt these critical entry pathways of SARS-CoV-2 spike glycoprotein interaction with human ACE2, could potentially accelerate the identification and clinical advancement of prophylactic and/or treatment options against COVID-19, thus providing possible countermeasures against viral entry, pathogenesis and survival. Herein, we discovered that Ambroxol hydrochloride (AMB), and its progenitor, Bromhexine hydrochloride (BHH), both clinically approved drugs are potent effective modulators of the key interaction between the receptor binding domain (RBD) of SARS-CoV-2 spike protein and human ACE2. We also found that both compounds inhibited SARS-CoV-2 infection-induced cytopathic effect at micromolar concentrations. Therefore, in addition to the known TMPRSS2 activity of BHH; we report for the first time that the BHH and AMB pharmacophore has the capacity to target and modulate yet another key protein-protein interaction essential for the two known SARS-CoV-2 entry pathways into host cells. Altogether, the potent efficacy, excellent safety and pharmacologic profile of both drugs along with their affordability and availability, makes them promising candidates for drug repurposing as possible prophylactic and/or treatment options against SARS-CoV-2 infection. ### Competing Interest Statement The authors have declared no competing interest.

17: Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region
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Posted 11 Jun 2020

Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region
190 downloads bioRxiv pharmacology and toxicology

Adriana Carino, Federica Moraca, Bianca Fiorillo, Silvia Marchianò, Valentina Sepe, Michele Biagioli, Claudia Finamore, Silvia Bozza, Daniela Francisci, Eleonora Distrutti, Bruno Catalanotti, Angela Zampella, Stefano Fiorucci

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors. ### Competing Interest Statement This paper was supported by a research grant by BAR Pharmaceuticals S.r.L. to the Department of Pharmacy of the University of Napoli Federico II and to the Department of Surgical and Biomedical Sciences, University of Perugia. The authors declare the following competing financial interest(s): S.F., A.Z. and B.C. have filed an Italian patent application no.102020000011092 in the name of BAR Pharmaceuticals S.r.L. on the compounds described in this paper.

18: The Effect Of Famotidine On SARS-CoV-2 Proteases And Virus Replication
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Posted 15 Jul 2020

The Effect Of Famotidine On SARS-CoV-2 Proteases And Virus Replication
188 downloads bioRxiv pharmacology and toxicology

Madeline Loffredo, Hector Lucero, Da-Yuan Chen, Aoife O’Connell, Simon Bergqvist, Ahmad Munawar, Asanga Bandara, Steff De Graef, Stephen D. Weeks, Florian Douam, Mohsan Saeed, Ali H. Munawar

The lack of coronavirus-specific antiviral drugs has instigated multiple drug repurposing studies to redirect previously approved medicines for the treatment of SARS-CoV-2, the coronavirus behind the ongoing COVID-19 pandemic. A recent, large-scale, retrospective clinical study showed that famotidine, when administered at a high dose to hospitalized COVID-19 patients, reduced the rates of intubation and mortality. A separate, patient-reported study associated famotidine use with improvements in mild to moderate symptoms such as cough and shortness of breath. While a prospective, multi-center clinical study is ongoing, two parallel in silico studies have proposed one of the two SARS-CoV-2 proteases, 3CLpro or PLpro, as potential molecular targets of famotidine activity; however, this remains to be experimentally validated. In this report, we systematically analyzed the effect of famotidine on viral proteases and virus replication. Leveraging a series of biophysical and enzymatic assays, we show that famotidine neither binds with nor inhibits the functions of 3CLpro and PLpro. Similarly, no direct antiviral activity of famotidine was observed at concentrations of up to 200 μM, when tested against SARS-CoV-2 in two different cell lines, including a human cell line originating from lungs, a primary target of COVID-19. These results rule out famotidine as a direct-acting inhibitor of SARS-CoV-2 replication and warrant further investigation of its molecular mechanism of action in the context of COVID-19. ### Competing Interest Statement The authors have declared no competing interest.

19: Human ACE2 peptide mimics block SARS-CoV-2 Pulmonary Cells Infection
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Posted 24 Aug 2020

Human ACE2 peptide mimics block SARS-CoV-2 Pulmonary Cells Infection
175 downloads bioRxiv pharmacology and toxicology

Philippe Karoyan, Vincent Vieillard, Estelle Odile, Alexis Denis, Amélie Guihot, Charles-Edouard Luyt, Luis Gómez-Morales, Pascal Grondin, Olivier Lequin

In the light of the recent accumulated knowledge on SARS-CoV-2 and its mode of human cells invasion, the binding of viral spike glycoprotein to human Angiotensin Converting Enzyme 2 (hACE2) receptor plays a central role in cell entry. We designed a series of peptides mimicking the N-terminal helix of hACE2 protein which contains most of the contacting residues at the binding site and have a high helical folding propensity in aqueous solution. Our best peptide mimics bind to the virus spike protein with high affinity and are able to block SARS-CoV-2 human pulmonary cell infection with an inhibitory concentration (IC50) in the nanomolar range. These first in class blocking peptide mimics represent powerful tools that might be used in prophylactic and therapeutic approaches to fight the coronavirus disease 2019 (COVID-19). ### Competing Interest Statement The authors declare the following competing financial interest(s): The patent application EP20305449.9 included results from this paper. The authors declare that no other competing interests exist.

20: PyVOL: a PyMOL plugin for visualization, comparison, and volume calculation of drug-binding sites
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Posted 24 Oct 2019

PyVOL: a PyMOL plugin for visualization, comparison, and volume calculation of drug-binding sites
173 downloads bioRxiv pharmacology and toxicology

Ryan H.B. Smith, Arvin C. Dar, Avner Schlessinger

Motivation: Binding pocket volumes are a simple yet important predictor of small molecule binding; however, generating visualizations of pocket topology and performing meaningful volume comparisons can be difficult with available tools. Current programs for accurate volume determination rely on extensive user input to define bulk solvent boundaries and to partition cavities into subpockets, increasing inter-user variability in measurements as well as time demands. Results: We developed PyVOL, a python package with a PyMOL interface and GUI, to visualize, to characterize, and to compare binding pockets. PyVOLs pocket identification algorithm is designed to maximize reproducibility through minimization of user-provided parameters, avoidance of grid-based methods, and automated sub-pocket identification. This approach permits efficient, scalable volume calculations. Availability: PyVOL is released under the MIT License. Source code and documentation are available through github (https://github.com/schlessingerlab/pyvol/) with distribution through PyPI (bio-pyvol). Contact: avner.schlessinger@mssm.edu, arvin.dar@mssm.edu

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