Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase

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

doi:10.1101/2020.04.03.022939

Cited by 33 publications

(43 citation statements)

References 26 publications

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“…Remdesivir is the first agent to show preliminary clinical efficacy in an NIH randomized, placebo-controlled study (Wang et al, 2020) and the FDA has approved its Emergency Use Authorization for hospitalized patients with severe COVID-19. Tenofovir and emtricitabine can inhibit the RdRp of SARS-CoV-2 in vitro (Jockusch et al, 2020), and expected from our in silico analyses.…”

Section: Discussionsupporting

confidence: 68%

“…It is to be expected that NNRTIs as a class did not bind well to the catalytic site for the SARS-CoV-2 RdRp, which is the nucleoside/nucleotide triphosphate (NTP) binding site, where elongation of the RNA strand occurs (Gao et al, 2020). When NRTIs are metabolized and form triphosphate structures, they are capable of being added to the growing RNA/DNA strand and chain termination will follow (Gordon et al, 2020;Jockusch et al, 2020;Wang et al, 2020). However, HIV reverse transcriptase is inhibited by NNRTIs at a site different from that which the NRTIs bind to.…”

Section: Discussionmentioning

confidence: 99%

“…However, a small randomized controlled clinical trial of lopinavir and ritonavir coadministered to hospitalized adults with severe COVID-19 showed no clinical benefit over the standard of care (Cao et al, 2020). A recent preprint reported that tenofovir and emtricitabine act as chain terminators in the replication of viral RNA by the SARS-CoV-2 RdRp (Jockusch et al, 2020). In silico studies help us to gauge projected mechanisms and likely molecules which bind to solved targets, in a cost effective, high throughput manner, ideal for primary analyses.…”

Section: Introductionmentioning

confidence: 99%

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Antiretroviral Drug Activity and Potential for Pre-Exposure Prophylaxis Against COVID-19 and HIV Infection

Copertino¹,

Lima²,

Duarte³

et al. 2020

Preprint

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<p>COVID-19 is the disease caused by SARS-CoV-2, and has led to over 250,000 deaths by May 2020. Urgent studies to identify new antiviral drugs, repurpose existing drugs, or identify those drugs that can specifically target the overactive immune response are ongoing around the world. Antiretroviral drugs (ARVs) have been tested in past human coronavirus infections, and also against SARS-CoV-2, but a recent clinical trial of lopinavir and ritonavir failed to show any clinical benefit in COVID-19 disease. However, anecdotal reports suggest either reduced infection or a course of milder COVID-19 disease in people living with HIV (PLWH) on ARVs. We hypothesized ARVs other than lopinavir and ritonavir might be responsible for such effects. Here, we used chemoinformatic analyses to predict which ARVs would bind and potentially inhibit the SARS-CoV-2 main protease or RNA-dependent RNA polymerase enzymes, and identified a number of ARVs which bind to SARS-CoV-2 enzymes in silico. Our study identified HIV nucleoside/nucleotide analogue reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, tenofovir, zidovudine), HIV protease inhibitors (ASC09, atazanavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) and an HIV pharmacokinetic booster (cobicistat), as drug candidates with effective in silico binding to one or both viral enzymes. Tenofovir and emtricitabine are FDA-approved as HIV pre-exposure prophylaxis (PrEP) and have an extensive safety profile of use in populations without HIV. Existing or new combinations of antiretroviral drugs could potentially prevent or ameliorate the course of COVID-19, if shown to inhibit SARS-CoV-2 in vitro and/or in clinical trials. Further studies are needed to establish the activity of ARVs for treatment or prevention of SARS-CoV-2 infection.</p>

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antiretroviral Drug Activity and Potential for Pre-Exposure Prophylaxis Against COVID-19 and HIV Infection

Copertino¹,

Lima²,

Duarte³

et al. 2020

Preprint

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“…If Car-TP, Gan-TP or Ent-TP is incorporated and acts as a terminator, extension will stop; otherwise additional incorporation events may be observed. Guided by polymerase extension results we obtained previously for the active triphosphate forms of Sofosbuvir, Alovudine, AZT, Tenofovir-DP and Emtricitabine-TP (Ju et al 2020;Chien et al 2020;Jockusch et al 2020), various ratios of the nucleotides were chosen in the current work.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine (Ju et al 2020;Chien et al 2020;Jockusch et al 2020). Emtricitabine and Tenofovir alafenamide are used in FDA approved combination regimens for treatment of HIV/AIDS and hepatitis B virus (HBV) infections as well as pre-exposure prophylaxis (PrEP) to prevent HIV infections (Anderson et al 2011), and may be evaluated for PrEP for COVID-19 (Jockusch et al 2020).…”

Section: Selection Of Candidate Nucleoside Triphosphates For Coronavimentioning

confidence: 99%

A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19

Jockusch

Tao

et al. 2020

Preprint

Self Cite

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SARS-CoV-2, a member of the coronavirus family, is responsible for the current COVID-19 worldwide pandemic. We previously demonstrated that five nucleotide analogues inhibit the SARS-CoV-2 RNAdependent RNA polymerase (RdRp), including the active triphosphate forms of Sofosbuvir, Alovudine, Zidovudine, Tenofovir alafenamide and Emtricitabine. We report here the evaluation of a library of additional nucleoside triphosphate analogues with a variety of structural and chemical features as inhibitors of the RdRps of SARS-CoV and SARS-CoV-2. These features include modifications on the sugar (2' or 3' modifications, carbocyclic, acyclic, or dideoxynucleotides) or on the base. The goal is to identify nucleotide analogues that not only terminate RNA synthesis catalyzed by these coronavirus RdRps, but also have the potential to resist the viruses' exonuclease activity. We examined these nucleotide analogues with regard to their ability to be incorporated by the RdRps in the polymerase reaction and then prevent further incorporation. While all 11 molecules tested displayed incorporation, 6 exhibited immediate termination of the polymerase reaction (Carbovir triphosphate, Ganciclovir triphosphate, Stavudine triphosphate, Entecavir triphosphate, 3'-O-methyl UTP and Biotin-16-dUTP), 2 showed delayed termination (Cidofovir diphosphate and 2'-O-methyl UTP), and 3 did not terminate the polymerase reaction (2'-fluoro-dUTP, 2'-amino-dUTP and Desthiobiotin-16-UTP). The coronavirus genomes encode an exonuclease that apparently requires a 2'-OH group to excise mismatched bases at the 3'-terminus. In this study, all of the nucleoside triphosphate analogues we evaluated form Watson-Cricklike base pairs. All the nucleotide analogues which demonstrated termination either lack a 2'-OH, have a blocked 2'-OH, or show delayed termination. These nucleotides may thus have the potential to resist exonuclease activity, a property that we will investigate in the future. Furthermore, prodrugs of five of these nucleotide analogues (Brincidofovir/Cidofovir, Abacavir, Valganciclovir/Ganciclovir, Stavudine and Entecavir) are FDA approved for other viral infections, and their safety profile is well known. Thus, they can be evaluated rapidly as potential therapies for COVID-19.

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Antiretrovirals for Prophylaxis Against COVID‐19: A Comprehensive Literature Review

Alavian

Kolahdouzan

Mortezazadeh

et al. 2020

The Journal of Clinical Pharma

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Although people living with human immunodeficiency virus(PLWH) and other comorbidities are expected to experience griever consequences with COVID-19, recent cohort studies do not indicate this. Antiretrovirals(ARVs) might have a prophylactic role in these patients. The purpose of this study is to review the most recently published articles on the possible role of ARVs for pre or post-exposure prophylaxis against COVID-19. From June to October 2020, we searched scientific databases using specific keywords to identify ongoing trials or articles published before October 2020 investigating any subgroups of ARVs for prophylaxis against COVID-19. Apart from molecular docking studies, in vitro, animal, and human studies are very limited for evaluating the prophylactic role of ARVs against SARS-CoV-2 infection. According to our findings, there is no definite evidence to support use of protease inhibitors for this purpose, despite the promising results of molecular studies and limited clinical evidence for ritonavir boosted lopinavir, darunavir, and nelfinavir when used early in the course of the disease. Nucleotide/nucleoside reverse transcriptase inhibitors(NRTI) also have shown binding affinity to SARS-CoV-2 main enzymes in molecular, in vitro and animal studies. NRTIs like tenofovir and emtricitabine might exhibit prophylactic role against SARS-CoV-2 infection. In This article is protected by copyright. All rights reserved. conclusion, currently there is no evidence to justify the use of ARVs for prophylaxis against COVID-19.

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Triphosphates of the Two Components in DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase

Cited by 33 publications

References 26 publications

Antiretroviral Drug Activity and Potential for Pre-Exposure Prophylaxis Against COVID-19 and HIV Infection

Antiretroviral Drug Activity and Potential for Pre-Exposure Prophylaxis Against COVID-19 and HIV Infection

A Library of Nucleotide Analogues Terminate RNA Synthesis Catalyzed by Polymerases of Coronaviruses Causing SARS and COVID-19

Antiretrovirals for Prophylaxis Against COVID‐19: A Comprehensive Literature Review

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