Putative Repurposing of Lamivudine, a Nucleoside/Nucleotide Analogue and Antiretroviral to Improve the Outcome of Cancer and COVID-19 Patients.

José J García-Trejo,Mariel Zarco-Zavala,Raquel Ortega

doi:10.3389/fonc.2021.664794

José J García-Trejo, Mariel Zarco-Zavala + Show 1 more

Open Access

https://doi.org/10.3389/fonc.2021.664794

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Abstract

Lamivudine, also widely known as 3TC belongs to a family of nucleotide/nucleoside analogues of cytidine or cytosine that inhibits the Reverse Transcriptase (RT) of retroviruses such as HIV. Lamivudine is currently indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection or for chronic Hepatitis B (HBV) virus infection associated with evidence of hepatitis B viral replication and active liver inflammation. HBV reactivation in patients with HBV infections who receive anticancer chemotherapy can be a life-threatening complication during and after the completion of chemotherapy. Lamivudine is used, as well as other antiretrovirals, to prevent the reactivation of the Hepatitis B virus during and after chemotherapy. In addition, Lamivudine has been shown to sensitize cancer cells to chemotherapy. Lamivudine and other similar analogues also have direct positive effects in the prevention of cancer in hepatitis B or HIV positive patients, independently of chemotherapy or radiotherapy. Recently, it has been proposed that Lamivudine might be also repurposed against SARS-CoV-2 in the context of the COVID-19 pandemic. In this review we first examine recent reports on the re-usage of Lamivudine or 3TC against the SARS-CoV-2, and we present docking evidence carried out in silico suggesting that Lamivudine may bind and possibly work as an inhibitor of the SARS-CoV-2 RdRp RNA polymerase. We also evaluate and propose assessment of repurposing Lamivudine as anti-SARS-CoV-2 and anti-COVID-19 antiviral. Secondly, we summarize the published literature on the use of Lamivudine or (3TC) before or during chemotherapy to prevent reactivation of HBV, and examine reports of enhanced effectiveness of radiotherapy in combination with Lamivudine treatment against the cancerous cells or tissues. We show that the anti-cancer properties of Lamivudine are well established, whereas its putative anti-COVID effect is under investigation. The side effects of lamivudine and the appearance of resistance to 3TC are also discussed.

Highlights

Drug repurposing takes advantage of previously FDA-approved drugs indicated for a particular illness, and focuses on using these drugs to improve the outcome of patients suffering a different disease
The safety profile is often well known, possibly making subsequent approval processes easier and more cost-effective. This is illustrated by some non-steroidal antiinflammatory drugs (NSAIDs) which have recently been shown to improve the treatment of cancer patients receiving chemotherapy [reviewed in [1]]
We found that Lamivudine (3TC) is not currently under COVID-19 clinical trials it has a reported inhibitory effect on the RNA-dependent-RNA polymerase (RdRp)-RNA polymerase of a related hepatitis virus [59]

Summary

Introduction

Drug repurposing takes advantage of previously FDA-approved drugs indicated for a particular illness, and focuses on using these drugs to improve the outcome of patients suffering a different disease. One last control was to carry out a docking of ATP on the NSP12, as this was necessary to find the relative affinity with which Remdesivir-TP will compete with ATP to inhibit the SARS-CoV-2-RdRp. In agreement with the previous dockings, the ATP docked at the catalytic site of the enzyme overlapping with the Remdesivir-MP observed by cryo-EM (see Figure 5B), with an estimated Kd of 5.95 × 10−10 and a DG° = −13.10 kcal/mol.

Results

Conclusion