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

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.

Approved HIV reverse transcriptase inhibitors in the past decade

“…(iii) NRTIs may reduce the risk of age-related macular degeneration that causes blindness in humans 167 . (iv) NRTIs such as lamivudine might be repurposed as anti-cancer drugs 168 . (v) HIV RT inhibitors have been initially proposed to treat coronavirus disease 2019 (COVID-19) 168 , 169 , which has caused a global pandemic with severe morbidity and mortality since the end of 2019 170 , 171 , 172 , 173 , 174 .…”

“…(iv) NRTIs such as lamivudine might be repurposed as anti-cancer drugs 168 . (v) HIV RT inhibitors have been initially proposed to treat coronavirus disease 2019 (COVID-19) 168 , 169 , which has caused a global pandemic with severe morbidity and mortality since the end of 2019 170 , 171 , 172 , 173 , 174 . As of today, no anti-HIV drug has been approved for the treatment of COVID-19 175 , whereas TDF + FTC could reduce the risk of COVID-19 and hospitalization in HIV-positive patients 176 .…”

Efficacious Preclinical Repurposing of the Nucleoside Analogue Didanosine against COVID-19 Polymerase and Exonuclease

“…However, another ddN analogue, which is the synthetic dideoxycytidine analogue lamivudine (3TC), has been proposed and in some instances demonstrated to be effective against the SARS-CoV-2 RdRp activity. 24 , 31 Furthermore, in one of these previous reports, not only 3TC but also DDI have been included in the list of ddNTP analogues suggested to be suitable to try against the SARS-CoV-2 RdRp. 31 Taken together, the present and previous results show that, although not being NTP analogues, the ddNTP analogues such as DDI or 3TC may exert very effective and unique biological inhibition of both principal activities, the RNA polymerase and RNA proofreading activities, of the SARS-CoV-2 RdRp, as a result of the lack of both essential adjacent hydroxyls, the 2′ and 3′ hydroxyls, in the ribose moiety of these analogues.…”

“… 24 , 31 Furthermore, in one of these previous reports, not only 3TC but also DDI have been included in the list of ddNTP analogues suggested to be suitable to try against the SARS-CoV-2 RdRp. 31 Taken together, the present and previous results show that, although not being NTP analogues, the ddNTP analogues such as DDI or 3TC may exert very effective and unique biological inhibition of both principal activities, the RNA polymerase and RNA proofreading activities, of the SARS-CoV-2 RdRp, as a result of the lack of both essential adjacent hydroxyls, the 2′ and 3′ hydroxyls, in the ribose moiety of these analogues. Therefore, one of the novelties of this paper is that DDI is presented as one of the first dideoxy analogues of the natural nucleoside/nucleotide substrates (ddNs and ddNTPs) of the SARS-CoV-2 RdRp proposed as a potent anti-SARS-CoV-2/anti-COVID-19 agent.…”

Substrate-Based Design of Cytosolic Nucleotidase IIIB Inhibitors and Structural Insights into Inhibition Mechanism

“…All 5’-nuclotidases have broad substrate specificity, and consequently, in addition to their physiological activity, can also dephosphorylate 5’-phosphate esters of therapeutically relevant nucleoside analogs [ 1 , 2 , 6 ]. This activity negatively affects pharmacological efficacy of nucleoside analogs and limits their clinical use [ 7 , 8 , 9 ]. 5’-Cytosolic nucleotidase IIIB (cN-IIIB) is one of the most recently discovered 5’-nucleotidases and has several unique structural and functional features.…”