key: cord-0838207-xn2cxgc0 authors: Khan, Suliman; Attar, Farnoosh; Bloukh, Samir Haj; Sharifi, Majid; Nabi, Faisal; Bai, Qian; Khan, Rizwan Hasan; Falahati, Mojtaba title: A review on the interaction of nucleoside analogues with SARS-CoV-2 RNA dependent RNA polymerase date: 2021-03-22 journal: Int J Biol Macromol DOI: 10.1016/j.ijbiomac.2021.03.112 sha: d260108916d25d3153d19c2d6bb7068c936dc55c doc_id: 838207 cord_uid: xn2cxgc0 The outbreaks of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) in 2019, have highlighted the concerns about the lack of potential vaccines or antivirals approved for inhibition of CoVs infection. SARS-CoV-2 RNA dependent RNA polymerase (RdRp) which is almost preserved across different viral species can be a potential target for development of antiviral drugs, including nucleoside analogues (NA). However, ExoN proofreading activity of CoVs leads to their protection from several NAs. Therefore, potential platforms based on the development of efficient NAs with broad-spectrum efficacy against human CoVs should be explored. This study was then aimed to present an overview on the development of NAs-based drug repurposing for targeting SARS-CoV-2 RdRp by computational analysis. Afterwards, the clinical development of some NAs including Favipiravir, Sofosbuvir, Ribavirin, Tenofovir, and Remdesivir as potential inhibitors of RdRp, were surveyed. Overall, exploring broad-spectrum NAs as promising inhibitors of RdRp may provide useful information about the identification of potential antiviral repurposed drugs against SARS-CoV-2. physicians choose the most appropriate treatment regimen for particular patients with different underlying medical conditions [29] [30] [31] [32] [33] . Different classes of inhibitors can be developed for the treatment of SARS-CoV-2 infection. These classes include enzyme inhibitors (including protease, polymerase, methyltransferase (MTase) and exonuclease inhibitors), receptor inhibitors and viral fusion inhibitors [34] [35] [36] . The physio-pathological roles of these inhibitors are tabulated in Table 1 . Physio-pathological role Ref. Inhibit the cleavages of the long polyprotein chains to provide necessary proteins for replication of the virus [37] Polymerase Inhibit viral replication [38] MTase Inhibit the prevention of recognition by the host innate immune system [39] Exonuclease Inhibit resistance to many of the available antivirals [40] Receptor Inhibit the binding of virus to the host cells [41] Viral fusion Inhibit the SARS-CoV-2 S protein-mediated cell-cell fusion [42] 3. RNA-dependent RNA polymerase (RdRp) The activity of RdRp is vital for +RNA viral replications. After CoV entry into the host cell, the viral RNA, which consists of 14 open reading frames (ORFs), is released into the cytoplasm for viral replication (Fig. 1A ) [43] . The ORFs 1a and 1b segments assemble two replication polyproteins which are further hydrolyzed in different non-structural proteins (nsps). The RdRp (nsp12) is involved in CoV genomes and protein synthesis [44] . RdRp is known to play a crucial role in the replication of RNA viruses [33] . The deep groove domain as the core segment of In this review we aimed to present an overview on the application of NAs as potential enzyme inhibitors used to be repurposed as promising candidates in inhibiting SARS-CoV-2 polymerase. In general NAs induce potential preventive effects on viral replication by three well-studied mechanisms ( Fig. 1 C) [46] . As for different CoVs, amino acid sequence similarity for viral RdRp ranges from 70 to 100%, it is suggested that NAs could promisingly act as wide-ranging inhibitors of CoV infection [47] . However, nsp14-ExoN proofreading activity of CoVs results in their protection from several NAs [48, 49] . To potentially inhibit CoVs, well-developed NAs should be designed to either less recognized by ExoN or interact with polymerase at a rate exceeding ExoN excision velocity. Some NAs are prodrugs, requiring intracellular phosphorylation to induce their antiviral effects [50, 51] . In some cases, intracellular phosphorylation is performed by several host enzymes that convert the prodrug into monophosphate, diphosphate, and finally the active trisphosphate forms Emtricitabine can serve as potential inhibitor of the SARS-CoV-2 RdRp [55] determined by mass spectrometry (MS) ( Fig. 2A) . Also, it has been revealed that rapid interaction of Favipiravir by viral RdRp leads to SARS-CoV-2 lethal mutagenesis [56] . Didanosine is one of the NAs whose administered dose in adults is based on body weight [57] . Repurposing Didanosine as a promising treatment for COVID-19 has been reported based on single-cell RNA sequencing outcomes [57] . Hu, et al. [58] reported that in the computational studies, Abacavir (sulfate) as a NA showed the [67] . Reprinted with permission form Refs [58, 67] . Development of advanced docking algorithms has helped in the molecular recognition of various nucleoside analogue drugs against key inhibitors of SARS-CoV-2, however the stability of the complex formed, viability of molecular interactions and mechanism has been further established by studying their dynamics. In their computational study performed by Zhang and Zhou [68] they have depicted the antiviral property of Remdesivir using molecular dynamics simulations [68] . It has been speculated that Remdesivir acts as a competitive inhibitor of RdRp against its natural inhibitor which is ATP. Free energy perturbation studies have shown that Remdesivir position [72] . A second mechanism of inhibition has also been proposed by Tchesnokov, et al. [38] . Increased concentrations of NTPs can adversely lower down the RdRp inhibition by Remdesivir. As a result, Remdesivir gets incorporated in the first transcription. It has been observed that upcoming UTP could not get incorporated opposite to Remdesivir residue. This is because of a significant steric clash with A558. This leads to a template dependent inhibition of SARS-CoV-2 RdRp [38] . The recent advancement of NAs with antiviral efficiency can result in the development of anti-SARS-CoV-2 therapies [74] . The intracellular activation by active phosphorylation and associated metabolism should be considered during development of NAs as antiviral drugs. Several NAs as potential inhibitors of RdRp, such as Favipiravir, Sofosbuvir, Ribavirin, Tenofovir, and Remdesivir, were shown to be potential candidates for the possible treatment of SARS-CoV-2. Table 2 shows the practical considerations of antiviral therapies done against SARS-CoV-2. In this paper, some potential NAs were introduced to be repurposed as promising therapeutic candidates for the treatment of COVID-19 based on their interaction with RdRp. Currently, a number of NAs have been studied to inhibit human CoV in vitro and proceed into clinical trials against SARS-CoV-2. However more well-developed NAs are still demanded, considering factors such as therapeutic impacts, adverse effects, feasible synthesis, less labor, and cost effectiveness. It can be suggested that these candidates can be considered for the clinical treatment of COVID-19. 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