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TDF/FTC/TAF COVID Inhibitors
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from Spanish researchers conducting Truvada study:
Hi Jules
Attached a summary about the biological basis for using TDF including references. There is also the epi rational. HIV infection does not appear to be a risk factor for COVID desptie high number of HIV+ >50 and multiple comorbidities. The molecule of remdesivir is similar to tenofovir
TDF as an antiviral against SARS-CoV-2
• No in vitro activity in Vero E6 cells1. Authors do not rule out possible activity of TDF in airway epithelial cells
• Molecular docking study suggest that TDF might be active because its tight union to SARS-CoV-2 RdRp2
• On study has reported that tenofovir triphosphate is an inhibitor of SARS-CoV-2 RdRp3
TDF as a possible immunomodulator
• One in vitro study found that tenofovir decreases inflamattory cytokine production (IL-8, IL-10 y MCP-1) in PBMCs and might shift cytokine balance towards IL-12. This shift would promote a Th1 response leading to production of IFNγ by T and NK cells. This effect could be positive for severe COVID-19 disease characterized by increases of IL-8, IL-10 and MCP-14
• One study in HIV negative persons showed that TDF/FTC treatment decreases inmmune activation, a mechanism that could contribue to its protective effect as PrEP5
• A rhesus macaque model suggested that TDF could have an
immunospreserving/immunomodulating effect independent of its antivial effect6. Immunomodulatin effects of tenofovir and related compounds have been demonstrated in murine models including an increase in NK cells activity.7
1 Choy K-T, Wong AY-L, Kaewpreedee P, Sia S-F, Chen D, Hui KPY, et al. Remdesivir, lopinavir, emetine,
and homoharringtonine inhibit SARS-CoV-2 replication in vitro. ANTIVIRAL RESEARCH 2020; :104786.
2 Elfiky AA. Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 RNA
dependent RNA polymerase (RdRp): A molecular docking study. Life Sci 2020; :117592.
3Jockusch S, Tao C, Li X, Anderson TK, Chien M, Kumar S, et al. Triphosphates of the Two Components in
DESCOVY and TRUVADA are Inhibitors of the SARS-CoV-2 Polymerase. bioRxiv 2020; 22:826-8.
https://www.biorxiv.org/content/10.1101/2020.04.03.022939v1
Abstract -
In summary, these results demonstrate that the nucleotide analogues TFV-DP and Ec-TP are permanent terminators for the SARS-CoV-2 RdRp catalyzed reaction.Given that Tenofovir diphosphate (TFV-DP), which is the common active triphosphate form of TAF or TDF, is much smaller than natural nucleoside triphosphates, we expect that it can easily fit within the active site of SARS-CoV-2 RdRp. Based on these analyses, we previously demonstrated the the ability of TFV-DP to inhibit the SARS-CoV-2 RdRp.11 This inhibitory effect was furthered confirmed in the current study.....once the TFV-DP was incorporated, there was no further extension, which confirms that it is a permanent terminator.....In the case of emtricitabine triphosphate (Ec-TP)
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.
Coronaviruses are single-strand RNA viruses that share properties with other RNA viruses such as the hepatitis C virus (HCV), West Nile virus, Marburg virus, HIV, Ebola virus, dengue virus, and rhinoviruses. Coronaviruses, HCV and the flaviviruses are positive-sense single-strand RNA viruses2,3 that share a similar replication mechanism requiring an RNA-dependent RNA polymerase (RdRp) catalyzed reaction.
RdRp in coronaviruses is a precise and well-defined drug target; the active site of the RdRp is highly conserved among different positive-sense RNA viruses and shares common structural features in these viruses.4 RdRps, including the coronavirus polymerase, have low fidelity,5 which enables them to recognize a variety of modified nucleotide analogues as substrates. Such nucleotide and nucleoside analogues may inhibit further RNA-polymerase catalyzed RNA replication and are therefore important candidate anti-viral agents.6-9
Based on these criteria, we previously tested the active triphosphate forms of Sofosbuvir, Alovudine and AZT with the RdRps of both SARS-CoV and SARS-CoV-2. These three triphosphates, 2'-F,Me-UTP, 3'-F-dTTP and 3'-N3-dTTP, all demonstrated the ability to be incorporated by these two coronavirus RdRps, and to block further incorporation.10,11 We also demonstrated the ability of the active triphosphate form of tenofovir, tenofovir diphosphate (TFV-DP), to inhibit the SARS-CoV-2 RdRp.11 Tenofovir prodrugs are often used in combination with the drug emtricitabine as anti-viral medications. We report here that the active triphosphate forms of both tenofovir and emtricitabine are inhibitors of the SARS-CoV-2 RdRp catalyzed reaction in side-by-side experiments.
4 Melchjorsen J, Risør MW, Søgaard OS, O'Loughlin KL, Chow S, Paludan SR, et al. Tenofovir selectively
regulates production of inflammatory cytokines and shifts the IL-12/IL-10 balance in human primary
cells. J Acquir Immune Defic Syndr 2011; 57:265-275.
5 Castillo-Mancilla JR, Meditz A, Wilson C, Zheng J-H, Palmer BE, Lee EJ, et al. Reduced immune
activation during tenofovir-emtricitabine therapy in HIV-negative individuals. J Acquir Immune Defic
Syndr 2015; 68:495-501.
6 Van Rompay KKA, Singh RP, Pahar B, Sodora DL, Wingfield C, Lawson JR, et al. CD8+-cell-mediated
suppression of virulent simian immunodeficiency virus during tenofovir treatment. Journal of Virology
2004; 78:5324-5337.
7 Calio, R., N. Villani, E. Balestra, F. Sesa, A. Holy, J. Balzarini, E. De Clercq, C. F. Perno, and V. Del Gobbo.
1994. Enhancement of natural killer activity and interferon induction by different acyclic nucleoside
phosphonates. Antivir. Res. 23:77-89.
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