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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 118,896 papers from 512,740 authors.

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in category pharmacology and toxicology

1,016 results found. For more information, click each entry to expand.

1: 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
26,581 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.

2: Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice
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Posted 04 Apr 2020

Fatal toxicity of chloroquine or hydroxychloroquine with metformin in mice
10,211 downloads bioRxiv pharmacology and toxicology

N.V Rajeshkumar, Shinichi Yabuuchi, Shweta G Pai, Anirban Maitra, Manuel Hidalgo, Chi V Dang

Guided by the principle of primum non nocere (first do no harm), we report a cautionary note on the potential fatal toxicity of chloroquine (CQ) or hydroxychloroquine (HCQ) in combination with anti-diabetic drug metformin. We observed that the combination of CQ or HCQ and metformin, which were used in our studies as potential anti-cancer drugs, killed 30-40% of mice. While our observations in mice may not translate to toxicity in humans, the reports that CQ or HCQ has anti-COVID-19 activity, the use of CQ resulting in toxicity and at least one death, and the recent Emergency Use Authorization (EUA) for CQ and HCQ by the US Food and Drug Administration (FDA) prompted our report. Here we report the lethality of CQ or HCQ in combination with metformin as a warning of its potential serious clinical toxicity. We hope that our report will be helpful to stimulate pharmacovigilance and monitoring of adverse drug reactions with the use of CQ or HCQ, particularly in combination with metformin.

3: Nelfinavir was predicted to be a potential inhibitor of 2019 nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation
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Posted 28 Jan 2020

Nelfinavir was predicted to be a potential inhibitor of 2019 nCov main protease by an integrative approach combining homology modelling, molecular docking and binding free energy calculation
9,008 downloads bioRxiv pharmacology and toxicology

Zhijian Xu, Cheng Peng, Yulong Shi, Zhengdan Zhu, Kaijie Mu, Xiaoyu Wang, Weiliang Zhu

2019-nCov has caused more than 80 deaths as of 27 January 2020 in China, and infection cases have been reported in more than 10 countries. However, there is no approved drug to treat the disease. 2019-nCov Mpro is a potential drug target to combat the virus. We built homology models based on SARS Mpro structures, and docked 1903 small molecule drugs to the models. Based on the docking score and the 3D similarity of the binding mode to the known Mpro ligands, 4 drugs were selected for binding free energy calculations. Both MM/GBSA and SIE methods voted for nelfinavir, with the binding free energy of -24.69±0.52 kcal/mol and -9.42±0.04 kcal/mol, respectively. Therefore, we suggested that nelfinavir might be a potential inhibitor against 2019-nCov Mpro.

4: Garcinia cambogia extract removes calcium oxalate kidney stones in both genetic and non-genetic Drosophila models of nephrolithiasis
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Posted 27 Nov 2018

Garcinia cambogia extract removes calcium oxalate kidney stones in both genetic and non-genetic Drosophila models of nephrolithiasis
6,839 downloads bioRxiv pharmacology and toxicology

Qiuxia Fan, Xiaoming Feng, Xizhen Hong, Siqiao Gong, Jianwei Tian, Fanfan Hou, Fujian Zhang

Kidney stone formers with family history have a high rate of stone recurrence after kidney stone removal surgery and there is no effective medication available for treatment. Here, we show that Garcinia cambogia extract (GCE) efficiently removes calcium oxalate kidney stones from Malpighian tubules in both genetic and non-genetic Drosophila models of nephrolithiasis, and hydroxycitrate -a major component of GCE, directly dissolves calcium oxalate stones in Drosophila Malpighian tubules ex vivo. Our study discovers a potential novel therapeutic strategy for the clinical treatment of nephrolithiasis and suggests that clinical-grade Garcinia cambogia extract could be used to treat patients with nephrolithiasis in the future.

5: Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening
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Posted 29 Jan 2020

Therapeutic Drugs Targeting 2019-nCoV Main Protease by High-Throughput Screening
6,448 downloads bioRxiv pharmacology and toxicology

Yan Li, Jinyong Zhang, Wei Wang, Haibo Li, Yun Shi, Gang Guo, Kaiyun Liu, Hao Zeng, Quanming Zou

2019 Novel Coronavirus (2019-nCoV) is a virus identified as the cause of the outbreak of pneumonia first detected in Wuhan, China. Investigations on the transmissibility, severity, and other features associated with this virus are ongoing. Currently, there is no vaccine or therapeutic antibody to prevent the infection, and more time is required to develop an effective immune strategy against the pathogen. In contrast, specific inhibitors targeting the key protease involved in replication and proliferation of the virus are the most effective means to alleviate the epidemic. The main protease of SARS-CoV is essential for the life cycle of the virus, which showed 96.1% of similarity with the main proteaseof 2019-nCoV, is considered to be an attractive target for drug development. In this study, we have identified 4 small molecular drugs with high binding capacity with SARS-CoV main protease by high-throughput screening based on the 8,000 clinical drug libraries, all these drugs have been widely used in clinical applications with guaranteed safety, which may serve as promising candidates to treat the infection of 2019-nCoV.

6: 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
5,383 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.

7: Novel Natural Product Discovery from Marine Sponges and their Obligate Symbiotic Organisms
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Posted 24 May 2014

Novel Natural Product Discovery from Marine Sponges and their Obligate Symbiotic Organisms
5,028 downloads bioRxiv pharmacology and toxicology

Regina R. Monaco, Rena F. Quinlan

Abstract: Discovery of novel natural products is an accepted method for the elucidation of pharmacologically active molecules and drug leads. Best known sources for such discovery have been terrestrial plants and microbes, accounting for about 85% of the approved natural products in pharmaceutical use (1), and about 60% of approved pharmaceuticals and new drug applications annually (2). Discovery in the marine environment has lagged due to the difficulty of exploration in this ecological niche. Exploration began in earnest in the 1950’s, after technological advances such as scuba diving allowed collection of marine organisms, primarily at a depth to about 15m. Natural products from filter feeding marine invertebrates and in particular, sponges, have proven to be a rich source of structurally unique pharmacologically active compounds, with over 16,000 molecules isolated thus far (3, 1) and a continuing pace of discovery at hundreds of novel bioactive molecules per year. All classes of pharmaceuticals have been represented in this discovery process, including antiprotazoals, pesticides, TGF-beta inhibitors, cationic channel blockers, anticancer, cytotoxic, antiviral, anti-inflammatory and antibacterial compounds. Important biosynthetic pathways found in sponges which give rise to these compounds include the terpenoid (4), fatty acid, polyketoid, quinone reductase, alkaloid, isoprenoid (5), and non-ribosomal protein synthase pathways. Keywords: natural products; marine sponges; drug discovery; terpenoids; carotenoids; polyketides; marine drug discovery

8: AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2
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Posted 08 Mar 2020

AI-aided design of novel targeted covalent inhibitors against SARS-CoV-2
4,589 downloads bioRxiv pharmacology and toxicology

Bowen Tang, Fengming He, Dongpeng Liu, Meijuan Fang, Zhen Wu, Dong Xu

The focused drug repurposing of known approved drugs (such as lopinavir/ritonavir) has been reported failed for curing SARS-CoV-2 infected patients. It is urgent to generate new chemical entities against this virus. As a key enzyme in the life-cycle of coronavirus, the 3C-like main protease (3CLpro or Mpro) is the most attractive for antiviral drug design. Based on a recently solved structure (PDB ID: 6LU7), we developed a novel advanced deep Q-learning network with the fragment-based drug design (ADQN-FBDD) for generating potential lead compounds targeting SARS-CoV-2 3CLpro. We obtained a series of derivatives from those lead compounds by our structure-based optimization policy (SBOP). All the 47 lead compounds directly from our AI-model and related derivatives based on SBOP are accessible in our molecular library at https://github.com/tbwxmu/2019-nCov. These compounds can be used as potential candidates for researchers in their development of drugs against SARS-CoV-2.

9: 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
4,344 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.

10: 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
3,628 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.

11: 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
3,601 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.

12: Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
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Posted 20 Apr 2020

Boceprevir, GC-376, and calpain inhibitors II, XII inhibit SARS-CoV-2 viral replication by targeting the viral main protease
3,554 downloads bioRxiv pharmacology and toxicology

Chunlong Ma, Michael D. Sacco, Brett Hurst, Julia A Townsend, Yanmei Hu, Tommy Szeto, Xiujun Zhang, Bart Tarbet, Michael T Marty, Yu Chen, Jun Wang

A novel coronavirus SARS-CoV-2, also called novel coronavirus 2019 (nCoV-19), started to circulate among humans around December 2019, and it is now widespread as a global pandemic. The disease caused by SARS-CoV-2 virus is called COVID-19, which is highly contagious and has an overall mortality rate of 6.96% as of May 4, 2020. There is no vaccine or antiviral available for SARS-CoV-2. In this study, we report our discovery of inhibitors targeting the SARS-CoV-2 main protease (Mpro). Using the FRET-based enzymatic assay, several inhibitors including boceprevir, GC-376, and calpain inhibitors II, and XII were identified to have potent activity with single-digit to submicromolar IC50 values in the enzymatic assay. The mechanism of action of the hits was further characterized using enzyme kinetic studies, thermal shift binding assays, and native mass spectrometry. Significantly, four compounds (boceprevir, GC-376, calpain inhibitors II and XII) inhibit SARS-CoV-2 viral replication in cell culture with EC50 values ranging from 0.49 to 3.37 μM. Notably, boceprevir, calpain inhibitors II and XII represent novel chemotypes that are distinct from known Mpro inhibitors. A complex crystal structure of SARS-CoV-2 Mpro with GC-376, determined at 2.15 Å resolution with three monomers per asymmetric unit, revealed two unique binding configurations, shedding light on the molecular interactions and protein conformational flexibility underlying substrate and inhibitor binding by Mpro. Overall, the compounds identified herein provide promising starting points for the further development of SARS-CoV-2 therapeutics. ### Competing Interest Statement J. W. and C. M. are inventors of a pending patent that claims the use of the identified compounds for COVID-19.

13: Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase
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Posted 14 Mar 2020

Nucleotide Analogues as Inhibitors of SARS-CoV Polymerase
3,532 downloads bioRxiv pharmacology and toxicology

Jingyue Ju, Xiaoxu Li, Shiv Kumar, Steffen Jockusch, Minchen Chien, Chuanjuan Tao, Irina Morozova, Sergey Kalachikov, Robert N. Kirchdoerfer, James J. Russo

SARS-CoV-2, a member of the coronavirus family, has caused a global public health emergency. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously reasoned that the FDA-approved heptatitis C drug EPCLUSA (Sofosbuvir/Velpatasvir) should inhibit coronaviruses, including SARS-CoV-2. Here, using model polymerase extension experiments, we demonstrate that the activated triphosphate form of Sofosbuvir is incorporated by low-fidelity polymerases and SARS-CoV RNA-dependent RNA polymerase (RdRp), and blocks further incorporation by these polymerases; the activated triphosphate form of Sofosbuvir is not incorporated by a host-like high-fidelity DNA polymerase. Using the same molecular insight, we selected two other anti-viral agents, Alovudine and AZT (an FDA approved HIV/AIDS drug) for evaluation as inhibitors of SARS-CoV RdRp. We demonstrate the ability of two HIV reverse transcriptase inhibitors, 3′-fluoro-3′-deoxythymidine triphosphate and 3′-azido-3′-deoxythymidine triphosphate (the active triphosphate forms of Alovudine and AZT), to be incorporated by SARS-CoV RdRp where they also terminate further polymerase extension. Given the 98% amino acid similarity of the SARS-CoV and SARS-CoV-2 RdRps, we expect these nucleotide analogues would also inhibit the SARS-CoV-2 polymerase. These results offer guidance to further modify these nucleotide analogues to generate more potent broad-spectrum anti-coronavirus agents.

14: Nucleotide Analogues as Inhibitors of Viral Polymerases
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Posted 31 Jan 2020

Nucleotide Analogues as Inhibitors of Viral Polymerases
3,491 downloads bioRxiv pharmacology and toxicology

Jingyue Ju, Shiv Kumar, Xiaoxu Li, Steffen Jockusch, James J. Russo

Coronaviruses such as the newly discovered virus from Wuhan, China, 2019-nCoV, and the viruses that cause SARS and MERS, have resulted in regional and global public health emergencies. Based on our molecular insight that the hepatitis C virus and the coronavirus use a similar viral genome replication mechanism, we reasoned that the FDA-approved drug EPCLUSA (Sofosbuvir/Velpatasvir) for the treatment of hepatitis C will also inhibit the above coronaviruses, including 2019-nCoV. To develop broad spectrum anti-viral agents, we further describe a novel strategy to design and synthesize viral polymerase inhibitors, by combining the ProTide Prodrug approach used in the development of Sofosbuvir with the use of 3′-blocking groups that we have previously built into nucleotide analogues that function as polymerase terminators.

15: Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase
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Posted 05 Apr 2020

Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase
3,410 downloads bioRxiv pharmacology and toxicology

Steffen Jockusch, Chuanjuan Tao, Xiaoxu Li, Thomas K. Anderson, Minchen Chien, Shiv Kumar, James J. Russo, Robert N. Kirchdoerfer, Jingyue Ju

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. We previously demonstrated that four nucleotide analogues (specifically, the active triphosphate forms of Sofosbuvir, Alovudine, AZT and Tenofovir alafenamide) inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp). Tenofovir and emtricitabine are the two components in DESCOVY and TRUVADA, the two FDA-approved medications for use as pre-exposure prophylaxis (PrEP) to prevent HIV infection. This is a preventative method in which individuals who are HIV negative (but at high-risk of contracting the virus) take the combination drug daily to reduce the chance of becoming infected with HIV. PrEP can stop HIV from replicating and spreading throughout the body. We report here that the triphosphates of tenofovir and emtricitabine, the two components in DESCOVY and TRUVADA, act as terminators for the SARS-CoV-2 RdRp catalyzed reaction. These results provide a molecular basis to evaluate the potential of DESCOVY and TRUVADA as PrEP for COVID-19.

16: 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
3,408 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.

17: Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase
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Posted 20 Mar 2020

Nucleotide Analogues as Inhibitors of SARS-CoV-2 Polymerase
3,186 downloads bioRxiv pharmacology and toxicology

Minchen Chien, Thomas K. Anderson, Steffen Jockusch, Chuanjuan Tao, Shiv Kumar, Xiaoxu Li, James J. Russo, Robert N. Kirchdoerfer, Jingyue Ju

SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 pandemic. Based on our analysis of hepatitis C virus and coronavirus replication, and the molecular structures and activities of viral inhibitors, we previously demonstrated that three nucleotide analogues inhibit the SARS-CoV RNA-dependent RNA polymerase (RdRp). Here, using polymerase extension experiments, we have demonstrated that the active triphosphate form of Sofosbuvir (a key component of the FDA approved hepatitis C drug EPCLUSA), is incorporated by SARS-CoV-2 RdRp, and blocks further incorporation. Using the same molecular insight, we selected the active triphosphate forms of three other anti-viral agents, Alovudine, AZT (an FDA approved HIV/AIDS drug) and Tenofovir alafenamide (TAF, an FDA approved drug for HIV and hepatitis B) for evaluation as inhibitors of SARS-CoV-2 RdRp. We demonstrated the ability of these three viral polymerase inhibitors, 3′-fluoro-3′-deoxythymidine triphosphate, 3′-azido-3′-deoxythymidine triphosphate and Tenofovir diphosphate (the active triphosphate forms of Alovudine, AZT and TAF, respectively) to be incorporated by SARS-CoV-2 RdRp, where they also terminate further polymerase extension. These results offer a strong molecular basis for these nucleotide analogues to be evaluated as potential therapeutics for COVID-19.

18: A New Big-Data Paradigm For Target Identification And Drug Discovery
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Posted 07 May 2017

A New Big-Data Paradigm For Target Identification And Drug Discovery
3,088 downloads bioRxiv pharmacology and toxicology

Neel S. Madhukar, Prashant K. Khade, Linda Huang, Kaitlyn Gayvert, Giuseppe Galletti, Martin Stogniew, Joshua E. Allen, Paraskevi Giannakakou, Olivier Elemento

Drug target identification is one of the most important aspects of pre-clinical development yet it is also among the most complex, labor-intensive, and costly. This represents a major issue, as lack of proper target identification can be detrimental in determining the clinical application of a bioactive small molecule. To improve target identification, we developed BANDIT, a novel paradigm that integrates multiple data types within a Bayesian machine-learning framework to predict the targets and mechanisms for small molecules with unprecedented accuracy and versatility. Using only public data BANDIT achieved an accuracy of approximately 90% over 2000 different small molecules - substantially better than any other published target identification platform. We applied BANDIT to a library of small molecules with no known targets and generated ~4,000 novel molecule-target predictions. From this set we identified and experimentally validated a set of novel microtubule inhibitors, including three with activity on cancer cells resistant to clinically used anti-microtubule therapies. We next applied BANDIT to ONC201 - an active anti-cancer small molecule in clinical development - whose target has remained elusive since its discovery in 2009. BANDIT identified dopamine receptor 2 as the unexpected target of ONC201, a prediction that we experimentally validated. Not only does this open the door for clinical trials focused on target-based selection of patient populations, but it also represents a novel way to target GPCRs in cancer. Additionally, BANDIT identified previously undocumented connections between approved drugs with disparate indications, shedding light onto previously unexplained clinical observations and suggesting new uses of marketed drugs. Overall, BANDIT represents an efficient and highly accurate platform that can be used as a resource to accelerate drug discovery and direct the clinical application of small molecule therapeutics with improved precision.

19: Enhancing Intracellular Accumulation and Target Engagement of PROTACs with Reversible Covalent Chemistry
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Posted 30 Dec 2019

Enhancing Intracellular Accumulation and Target Engagement of PROTACs with Reversible Covalent Chemistry
3,062 downloads bioRxiv pharmacology and toxicology

Wen-Hao Guo, Xiaoli Qi, Xin Yu, Yang Liu, Chan-I Chung, Fang Bai, Xingcheng Lin, Dong Lu, Lingfei Wang, Jianwei Chen, Lynn Hsiao Su, Krystle J. Nomie, Feng Li, Meng C. Wang, Xiaokun Shu, José N. Onuchic, Jennifer A. Woyach, Michael L. Wang, Jin Wang

Current efforts in the proteolysis targeting chimera (PROTAC) field mostly focus on choosing an appropriate E3 ligase for the target protein, improving the binding affinities towards the target protein and the E3 ligase, and optimizing the PROTAC linker. However, due to the large molecular weights of PROTACs, their cellular uptake remains an issue. Through comparing how different warhead chemistry, reversible noncovalent (RNC), reversible covalent (RC), and irreversible covalent (IRC) binders, affects the degradation of Bruton’s Tyrosine Kinase (BTK), we serendipitously discover that cyano-acrylamide-based reversible covalent chemistry can significantly enhance the intracellular accumulation and target engagement of PROTACs and develop RC-1 as a reversible covalent BTK PROTAC with a high target occupancy as its corresponding kinase inhibitor and effectiveness as a dual functional inhibitor and degrader, a different mechanism-of-action for PROTACs. Importantly, this reversible covalent strategy is generalizable to improve other PROTACs, opening a path to enhance PROTAC efficacy. ### Competing Interest Statement J.W., W.G., X.Q., M.L.W., K.N., and Y.L. are the co-inventors of a patent related to this work. J.W. is the co-founder of CoActigon Inc. and Chemical Biology Probes LLC. X.S. and C.-I.C. have filed a patent application covering the SPPIER assay. M.L.W. receives research grants from Janssen, Pharmacyclics, AstraZeneca, Acerta Pharma, Celgene, Juno Therapeutics, BeiGene, Kite Pharma, Loxo Oncology, VelosBio, BioInvent, Aviara, Verastem, and InnoCare, consults and/or serves on the advisory board for Consulting/Advisory Board for Loxo Oncology, Janssen, Pharmacyclics, BioInvent, Celgene, Juno Therapeutics, Pulse Biosciences, MoreHealth, Guidepoint Global, Kite Pharma, AstraZeneca, Acerta Pharma, and InnoCare, received honoraria from Janssen, Acerta Pharma, OMI, Physicians Education Resources (PER), Oncology News, and Targeted Oncology, and owns stocks from MoreHealth. J.A.W. consults for Janssen, Pharmacyclics, Abbvie, AstraZeneca, and Arqule, receives research funding from Loxo Oncology and Abbvie and clinical trial funding from Pharmacyclics, Janssen, Verastem, Karyopharm, and Morphosys.

20: Traffic-derived particulate matter and angiotensin-converting enzyme 2 expression in human airway epithelial cells
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Posted 15 May 2020

Traffic-derived particulate matter and angiotensin-converting enzyme 2 expression in human airway epithelial cells
2,799 downloads bioRxiv pharmacology and toxicology

L Miyashita, G Foley, S Semple, Jonathan Grigg

Background: The mechanism for the association between traffic-derived particulate matter less than 10 microns (PM10) and cases of COVID-19 disease reported in epidemiological studies is unknown. To infect cells, the spike protein of SARS-CoV-2 interacts with angiotensin-converting enzyme 2 (ACE2) on host airway cells. Increased ACE2 expression in lower airway cells in active smokers, suggests a potential mechanism whereby PM10 increases vulnerability to COVID-19 disease. Objective: To assess the effect of traffic-derived PM10 on human airway epithelial cell ACE2 expression in vitro. Methods: PM10 was collected from Marylebone Road (London) using a kerbside impactor. A549 and human primary nasal epithelial cells were cultured with PM10 for 2 h, and ACE2 expression (median fluorescent intensity; MFI) assessed by flow cytometry. We included cigarette smoke extract as a putative positive control. Data were analysed by either Mann-Whitney test, or Kruskal-Wallis with multiple comparisons test. Results: PM10 at 10 μg/mL, and 20 μg/mL increased ACE2 expression in A549 cells (P<0.05, 0.01 vs. medium control, respectively). Experiments using a single PM10 concentration (10 μg/mL), found increased ACE2 expression in both A549 cells (control vs. PM10, median (IQR) MFI; 470 (0.1 to 1114) vs 6217 (5071 to 8506), P<0.01), and in human primary epithelial cells (0 (0 to 591) vs. 4000 (2610 to 7853), P<0.05). Culture of A549 cells with 5% cigarette smoke extract increased ACE2 expression (n=4, 0 (0 to 28) vs. 9088 (7557 to 15831, P<0.05). Conclusion: Traffic-related PM10 increases the expression of the receptor for SARS-CoV-2 in human respiratory epithelial cells. ### Competing Interest Statement The authors have declared no competing interest.

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