Tenofovir, Another Inexpensive, Well-Known and Widely Available Old Drug Repurposed for SARS-COV-2 Infection

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is spreading worldwide with different clinical manifestations. Age and comorbidities may explain severity in critical cases and people living with human immunodeficiency virus (HIV) might be at particularly high risk for severe progression. Nonetheless, current data, although sometimes contradictory, do not confirm higher morbidity, risk of more severe COVID-19 or higher mortality in HIV-infected people with complete access to antiretroviral therapy (ART). A possible protective role of ART has been hypothesized to explain these observations. Anti-viral drugs used to treat HIV infection have been repurposed for COVID-19 treatment; this is also based on previous studies on severe acute respiratory syndrome virus (SARS-CoV) and Middle East respiratory syndrome virus (MERS-CoV). Among them, lopinavir/ritonavir, an inhibitor of viral protease, was extensively used early in the pandemic but it was soon abandoned due to lack of effectiveness in clinical trials. However, remdesivir, a nucleotide analog that acts as reverse-transcriptase inhibitor, which was tested early during the pandemic because of its wide range of antiviral activity against several RNA viruses and its safety profile, is currently the only antiviral medication approved for COVID-19. Tenofovir, another nucleotide analog used extensively for HIV treatment and pre-exposure prophylaxis (PrEP), has also been hypothesized as effective in COVID-19. No data on tenofovir's efficacy in coronavirus infections other than COVID-19 are currently available, although information relating to SARS-CoV-2 infection is starting to come out. Here, we review the currently available evidence on tenofovir's efficacy against SARS-CoV-2.

Keywords: COVID-19 treatment; RNA-dependent RNA polymerase inhibitors; nucleoside/nucleotide analogues; nucleotide SARS-CoV-2; tenofovir.

Figure 1

(a) SARS-CoV-2 is an enveloped positive-sense single-stranded RNA virus. In mature virions, structural proteins surround and interact with the viral genome (spike (S), envelope (E), membrane (M) and nucleocapsid (N) proteins). Virions enter target cells after specific binding of the receptor-binding domain (RBD) of the viral protein S to the cellular entry receptor, the angiotensin-converting enzyme 2 (ACE2). Viral uptake is promoted by the proteolytic activity of host factors, like the cell-surface transmembrane serine protease 2 (TMPRSS2), whose enzymatic activity is essential to permit the fusion with the cellular membrane and virus entry. Once entered target cells, virions are uncoated and viral RNA is released in the cytosol and immediately translated into two large polyproteins, pp1a and pp1ab, specified by two large open reading frames of the viral RNA, ORF1a and ORF1b. Both polyproteins contain the amino acid sequences of viral non-structural proteins (nsps). pp1a contains nsp1 to nsp11, while pp1ab contains nsp1 to nsp10 and nsp12 to nsp16. These polyproteins are co-translationally and post-translationally processed through proteolytic cleavage by two viral cysteine proteases residing in the nsp3 and nsp5 sequence, the papain-like protease (PLpro) and the main protease or 3C-like protease (Mpro/3CLpro), respectively. Released nsp1 inhibits host mRNA translation, while nsp2 to nsp16 are involved in the intracellular viral replication cycle; in particular, nsp12 is the RNA dependent RNA polymerase (RdRp) that with the cofactors nsp7 and nsp8 performs viral RNA synthesis for translation and synthesis of structural and accessory proteins and for the assembly of new virions. (b) SARS-CoV-2 genome and protein organization.

Figure 2

Chemical structures of tenofovir, tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF).

Figure 3

Flow chart of database searching and screening of studies for the systematic review.