Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

Peters, H. L.; Jochmans, Dirk; Wilde, Adriaan H. de; Posthuma, Clara C.; Snijder, Eric J.; Neyts, Johan; Seley‐Radtke, Katherine L.

doi:10.1016/j.bmcl.2015.05.039

Cited by 77 publications

(90 citation statements)

References 24 publications

(27 reference statements)

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“…Other NIs with in vitro activity against CoVs and low cytotoxicity include the adenosine analogue BCX4430, which has broad spectrum activity against positive and negative sense RNA viruses and has shown antiviral activity against MERS-CoV and SARS-CoV [31,39]; the deoxycytidine analogue gemcitabine hydrochloride, a chemotherapy drug that inhibits SARS-CoV and MERS-CoV [40]; the uridine analogue 6-azauridine with activity against HCoV-NL63 [36]; and the immunosuppressant imidazole nucleoside mizoribine which inhibits SARS-CoV (Table 1) [18]. Flex-base modification of the guanosine analog acyclovir (acyclovir fleximer) yielded activity against HCoV-NL63 and MERS-CoV (Table 1) [41]. More research into the efficacy, potency, and mechanism of CoV inhibition is necessary to determine whether further development of these compounds as CoV antivirals is warranted.…”

Section: Nucleotide and Nucleoside Analogue Inhibitors For The Treatmmentioning

confidence: 99%

Nucleoside analogues for the treatment of coronavirus infections

Pruijssers

Denison

2019

Current Opinion in Virology

174

168

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Section: Nucleotide and Nucleoside Analogue Inhibitors For The Treatmmentioning

confidence: 99%

Nucleoside analogues for the treatment of coronavirus infections

Pruijssers

Denison

2019

Current Opinion in Virology

174

168

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“…The adenosine analogue BCX4430 inhibits CoV-induced cell death with an EC 50 (half maximal effective concentration) of 58 and 68 M for MERS-and SARS-CoV, respectively (Warren et al, 2014), whereas GS-5734, an adenosine monophosphate analogue, proved to be strikingly efficient at inhibiting MERS-CoV replication with an EC 50 of 0.34 M (Warren et al, 2016). The third compound with anti-CoV activity is a so-called flexible purine base analogue (fleximer), combined with the acyclic sugar moiety of acyclovir, which was capable of inhibiting HCoV-NL63 and MERS-CoV (but not SARS-CoV) replication with EC 50 values of 9 and 23-25 M, respectively, while acyclovir was inactive (Peters et al, 2015).…”

Section: Inhibitors Of Nidovirus Rna Polymerase Activitymentioning

confidence: 99%

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

2017

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Coronaviruses and arteriviruses are distantly related human and animal pathogens that belong to the order Nidovirales. Nidoviruses are characterized by their polycistronic plus-stranded RNA genome, the production of subgenomic mRNAs and the conservation of a specific array of replicase domains, including key RNA-synthesizing enzymes. Coronaviruses (26-34 kilobases) have the largest known RNA genomes and their replication presumably requires a processive RNA-dependent RNA polymerase (RdRp) and enzymatic functions that suppress the consequences of the typically high error rate of viral RdRps. The arteriviruses have significantly smaller genomes and form an intriguing package with the coronaviruses to analyse viral RdRp evolution and function. The RdRp domain of nidoviruses resides in a cleavage product of the replicase polyprotein named non-structural protein (nsp) 12 in coronaviruses and nsp9 in arteriviruses. In all nidoviruses, the C-terminal RdRp domain is linked to a conserved N-terminal domain, which has been coined NiRAN (nidovirus RdRp-associated nucleotidyl transferase). Although no structural information is available, the functional characterization of the nidovirus RdRp and the larger enzyme complex of which it is part, has progressed significantly over the past decade. In coronaviruses several smaller, non-enzymatic nsps were characterized that direct RdRp function, while a 3'-to-5' exoribonuclease activity in nsp14 was implicated in fidelity. In arteriviruses, the nsp1 subunit was found to maintain the balance between genome replication and subgenomic mRNA production. Understanding RdRp behaviour and interactions during RNA synthesis and subsequent processing will be key to rationalising the evolutionary success of nidoviruses and the development of antiviral strategies.

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“…Recently, these inhibitors are screened for their capability to inhibit Mpro and treat SARS infection using in vivo, in vitro, and in silico experiments (34)(35)(36)(37)(38)(39). The clinical trial of LPV showed a significant decrease in virus titer, reduced rate of death, and improved clinical recovery (40)(41)(42). In this direction, it deemed appropriate to study in detail the molecular interactions between Mpro coordinate structure and HIV-1 protease inhibitors using femtosecond snapshots of MD simulations trajectories.…”

Section: Discussionmentioning

confidence: 99%

Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study

Dayer

Taleb-Gassabi

Dayer

2017

Arch Clin Infect Dis

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Background: The severe acute respiratory syndrome (SARS) is a life threatening viral infection caused by a positive, single stranded RNA virus from the enveloped coronaviruse family. Associated with fever, cough, and respiratory complications, the illness causes more than 15% mortality worldwide. So far, there is no remedy for the illness except supportive treatments. However, the main viral proteinase has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction. Objectives: The present in silico study was designed to evaluate the effects of anti HIV-1 proteases inhibitors, approved for clinical applications by US FDA, on SARS proteinase inhibition. Methods: In the present study, docking and molecular dynamic experiments were applied to examine the effect of inhibitors on coronavirus proteinase under physiological conditions of similar pH, temperature, and pressure in aqueous solution. Hex software version 5.1 and GROMACS 4.5.5 were used for docking analysis throughout this work. Results:The calculated parameters such as RMSD, RMSF, MSD, dipole moment, diffusion coefficient, binding energy, and binding site similarity indicated effective binding of inhibitors to SARS proteinase resulting in their structural changes, which coincide with proteinase inhibition. Conclusions:The inhibitory potency of HIV 1 protease inhibitors to cronovirus proteinase was as follows: LPV > RTV > APV > TPV > SQV. Lopinavir and Saquinavir were the most and the least powerful inhibitors of cronovirus proteinase, respectively.

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Design, synthesis and evaluation of a series of acyclic fleximer nucleoside analogues with anti-coronavirus activity

Cited by 77 publications

References 24 publications

Nucleoside analogues for the treatment of coronavirus infections

Nucleoside analogues for the treatment of coronavirus infections

Nidovirus RNA polymerases: Complex enzymes handling exceptional RNA genomes

Lopinavir; A Potent Drug against Coronavirus Infection: Insight from Molecular Docking Study

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