Comparative Antiviral Activity of Remdesivir and Anti-HIV Nucleoside Analogs against Human Coronavirus 229E (HCoV-229E)

Remdesivir is a nucleotide prodrug that is currently undergoing extensive clinical trials for the treatment of COVID-19. The prodrug is metabolized to its active triphosphate form and interferes with the action of RNA-dependent RNA polymerase of SARS-COV-2. Herein, we report the antiviral activity of remdesivir against human coronavirus 229E (HCoV-229E) compared to known anti-HIV agents. These agents included tenofovir (TFV), 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA), alovudine (FLT), lamivudine (3TC), and emtricitabine (FTC), known as nucleoside reverse-transcriptase inhibitors (NRTIs), and a number of 5′-O-fatty acylated anti-HIV nucleoside conjugates. The anti-HIV nucleosides interfere with HIV RNA-dependent DNA polymerase and/or act as chain terminators. Normal human fibroblast lung cells (MRC-5) were used to determine the cytotoxicity of the compounds. The study revealed that remdesivir exhibited an EC50 value of 0.07 µM against HCoV-229E with TC50 of > 2.00 µM against MRC-5 cells. Parent NRTIs were found to be inactive against (HCoV-229E) at tested concentrations. Among all the NRTIs and 5′-O-fatty acyl conjugates of NRTIs, 5′-O-tetradecanoyl ester conjugate of FTC showed modest activity with EC50 and TC50 values of 72.8 µM and 87.5 µM, respectively. These data can be used for the design of potential compounds against other coronaviruses.

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Synthesis and Antiviral Activity of 1,3-Disubstituted Uracils against HIV-1 and HCMV

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632020301400506 ◽

2003 ◽

Vol 14 (5) ◽

pp. 271-279 ◽

Cited By ~ 15

Author(s):

Tokumi Maruyama ◽

Shigetada Kozai ◽

Tetsuo Yamasaki ◽

Myriam Witvrouw ◽

Christophe Pannecouque ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Human Cytomegalovirus ◽

Therapeutic Agents ◽

Reverse Transcriptase Inhibitors ◽

Uracil Derivatives ◽

Immunodeficiency Virus ◽

Anti Hiv Agents ◽

Anti Hiv ◽

Hiv 1

The development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) is an efficient strategy for finding new therapeutic agents against human immunodeficiency virus (HIV). A large number of 6-substituted uracil derivatives have been prepared in order to explore new NNRTIs. However, there are few approaches to anti-HIV agents from 1,3-disubstituted uracil derivatives. Therefore, we tried to prepare several 1,3-disubstituted uracils, which were easily obtainable from uracil by preparation under alkali and Mitsunobu conditions, and examined their antiviral activity against HIV-1 and human cytomegalovirus (HCMV). We found that 1-benzyl-3-(3,5-dimethylbenzyl)uracil and 1-cyanomethyl-3-(3,5-dimethylbenzyl)-4-thiouracil showed powerful inhibition against HCMV and HIV-1, respectively.

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Phenyl phosphoramidate derivatives of stavudine as anti-HIV agents with potent and selective in-vitro antiviral activity against Adenovirus

European Journal of Medicinal Chemistry ◽

10.1016/j.ejmech.2003.12.002 ◽

2004 ◽

Vol 39 (3) ◽

pp. 225-234 ◽

Cited By ~ 10

Author(s):

Fatih M. Uckun ◽

Sharon Pendergrass ◽

Sanjive Qazi ◽

P. Samuel ◽

T.K. Venkatachalam

Keyword(s):

Antiviral Activity ◽

Anti Hiv Agents ◽

Derivatives Of ◽

Anti Hiv

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Mechanism of Anti-Human Immunodeficiency Virus Activity of β-d-6-Cyclopropylamino-2′,3′-Didehydro-2′,3′-Dideoxyguanosine

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.49.5.1994-2001.2005 ◽

2005 ◽

Vol 49 (5) ◽

pp. 1994-2001 ◽

Cited By ~ 4

Author(s):

Adrian S. Ray ◽

Brenda I. Hernandez-Santiago ◽

Judy S. Mathew ◽

Eisuke Murakami ◽

Carey Bozeman ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Oral Delivery ◽

Mononuclear Cells ◽

Cellular Metabolism ◽

Nucleoside Analogs ◽

Immunodeficiency Virus ◽

Moderate Resistance ◽

Hiv Drugs ◽

Anti Hiv

ABSTRACT To better understand the importance of the oxygen in the ribose ring of planar unsaturated nucleoside analogs that target human immunodeficiency virus (HIV), a 6-cyclopropyl-substituted prodrug of 2′,3′-didehydro-2′,3′-dideoxyguanosine (cyclo-d4G) was synthesized, and its cellular metabolism, antiviral activity, and pharmacokinetic behavior were studied. Cyclo-d4G had selective anti-HIV activity in primary blood mononuclear cells (PBMCs), effectively inhibiting the LAI strain of HIV-1 by 50% at 1.1 ± 0.1 μM while showing 50% inhibition of cell viability at 84.5 μM. The antiviral activity in PBMCs was not markedly affected by mutations of methionine to valine at position 184 or by thymidine-associated mutations in the viral reverse transcriptase. Mutations of leucine 74 to valine and of lysine 65 to arginine had mild to moderate resistance (as high as fivefold). Studies to delineate the mechanism of cellular metabolism and activation of cyclo-d4G showed reduced potency in inhibiting viral replication in the presence of the adenosine/adenylate deaminase inhibitor 2′-deoxycoformycin, implying that the antiviral activity is due to its metabolism to the 2′-dGTP analog d4GTP. Intracellular formation of sugar catabolites illustrates the chemical and potentially enzymatic instability of the glycosidic linkage in d4G. Further studies suggest that cyclo-d4G has a novel intracellular phosphorylation pathway. Cyclo-d4G had a lower potential to cause mitochondrial toxicity than 2′,3′-dideoxycytidine and 2′,3′-didehydro-3′-deoxythymidine in neuronal cells. Also, cyclo-d4G had advantageous synergism with many currently used anti-HIV drugs. Poor oral bioavailability observed in rhesus monkeys may be due to the labile glycosidic bond, and special formulation may be necessary for oral delivery.

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Combination chemotherapy: Antiviral activity of AZT in combination with other anti-HIV agents

Antiviral Research ◽

10.1016/0166-3542(92)90132-o ◽

1992 ◽

Vol 17 ◽

pp. 61

Keyword(s):

Antiviral Activity ◽

Combination Chemotherapy ◽

Anti Hiv Agents ◽

Anti Hiv

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Phenyl Phosphoramidate Derivatives of Stavudine as anti-HIV Agents with Potent and Selective in-vitro Antiviral Activity Against Adenovirus.

ChemInform ◽

10.1002/chin.200435210 ◽

2004 ◽

Vol 35 (35) ◽

Author(s):

Fatih M. Uckun ◽

Sharon Pendergrass ◽

Sanjive Qazi ◽

P. Samuel ◽

T. K. Venkatachalam

Keyword(s):

Antiviral Activity ◽

Anti Hiv Agents ◽

Derivatives Of ◽

Anti Hiv

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Metabolism of 2′,3′-Dideoxy-2′,3′-Didehydro-β-l(−)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus β-d(+) Nucleoside Analogs In Vitro

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.7.1799 ◽

1998 ◽

Vol 42 (7) ◽

pp. 1799-1804 ◽

Cited By ~ 33

Author(s):

Ginger E. Dutschman ◽

Edward G. Bridges ◽

Shwu-Huey Liu ◽

Elizabeth Gullen ◽

Xin Guo ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Antiviral Activity ◽

Nucleoside Analogs ◽

Drug Combinations ◽

Mitochondrial Toxicity ◽

Hiv Reverse Transcriptase ◽

Immunodeficiency Virus ◽

Deoxycytidine Deaminase ◽

Anti Hiv

ABSTRACT 2′,3′-Dideoxy-2′,3′-didehydro-β-l(−)-5-fluorocytidine [l(−)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of l(−)Fd4C plus 2′,3′-didehydro-2′,3′-dideoxythymidine (D4T, or stavudine) or 3′-azido-3′-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with l(−)Fd4C in combination with 2′,3′-dideoxycytidine (ddC, or zalcitabine) or 2′,3′-dideoxyinosine (ddI, or didanosine). This β-l(−) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 μM. As we previously reported for other β-l(−) nucleoside analogs, l(−)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the Km is 100 μM.l(−)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also,l(−)Fd4C was not a substrate for deoxycytidine deaminase.l(−)Fd4C 5′-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by l(−)Fd4C in two-drug combinations favors the further development of l(−)Fd4C as an anti-HIV agent.

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Continuously Active Disinfectant Inactivates SARS-CoV-2 and Human Coronavirus 229E Two Days After the Disinfectant Was Applied and Following Wear Exposures

Infection Control and Hospital Epidemiology ◽

10.1017/ice.2021.481 ◽

2021 ◽

pp. 1-9

Author(s):

William A. Rutala ◽

Luisa A. Ikner ◽

Curtis J. Donskey ◽

David J. Weber ◽

Charles P. Gerba

Keyword(s):

Antiviral Activity ◽

Contact Time ◽

Human Coronavirus ◽

Human Coronavirus 229E ◽

Surface Environment

Abstract The surface environment in COVID-19 patient’s rooms may be persistently contaminated despite disinfection. A continuously active disinfectant demonstrated excellent sustained antiviral activity following a 48-hour period of wear and abrasion exposures with reinoculations. Reductions of >4-log10 were achieved within a 1-minute contact time for SARS-CoV-2 and the human coronavirus, 229E.

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