Flexibility as a Strategy in Nucleoside Antiviral Drug Design

Peters, H. L.; Ku, Therese; Seley‐Radtke, Katherine L.

doi:10.2174/0929867322666150818103624

Cited by 15 publications

(8 citation statements)

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“…It was then found that fleximers can bind to atypical enzymes and that they can overcome point mutations, which usually confer resistance to the rigid nucleoside analogue. 183 Further, broad-spectrum antiviral activity may be achieved through the fleximers’ ability to take part in “mutually induced fit”. 182 Combining the split purine base with an acyclic glycon (as found in the anti-herpesvirus drug acyclovir) has led to promising activity against members of different RNA virus families, including Filo -, Flavi-, and Coronaviridae .…”

Section: Targeting Viral Rna Synthesis With Direct-acting Antiviral Nmentioning

confidence: 99%

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Huchting

2020

Antivir Chem Chemother

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Zoonotic spillover, i.e. pathogen transmission from animal to human, has repeatedly introduced RNA viruses into the human population. In some cases, where these viruses were then efficiently transmitted between humans, they caused large disease outbreaks such as the 1918 flu pandemic or, more recently, outbreaks of Ebola and Coronavirus disease. These examples demonstrate that RNA viruses pose an immense burden on individual and public health with outbreaks threatening the economy and social cohesion within and across borders. And while emerging RNA viruses are introduced more frequently as human activities increasingly disrupt wild-life eco-systems, therapeutic or preventative medicines satisfying the “one drug-multiple bugs”-aim are unavailable. As one central aspect of preparedness efforts, this review digs into the development of broadly acting antivirals via targeting viral genome synthesis with host- or virus-directed drugs centering around nucleotides, the genomes’ universal building blocks. Following the first strategy, selected examples of host de novo nucleotide synthesis inhibitors are presented that ultimately interfere with viral nucleic acid synthesis, with ribavirin being the most prominent and widely used example. For directly targeting the viral polymerase, nucleoside and nucleotide analogues (NNAs) have long been at the core of antiviral drug development and this review illustrates different molecular strategies by which NNAs inhibit viral infection. Highlighting well-known as well as recent, clinically promising compounds, structural features and mechanistic details that may confer broad-spectrum activity are discussed. The final part addresses limitations of NNAs for clinical development such as low efficacy or mitochondrial toxicity and illustrates strategies to overcome these.

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Section: Targeting Viral Rna Synthesis With Direct-acting Antiviral Nmentioning

confidence: 99%

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Huchting

2020

Antivir Chem Chemother

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“…Efforts are globally underway to create an efficient vaccine or drug for prevention or treatment of the SARS infection (31)(32)(33). In this context, many reports showed that Mpro is an ideal target for drug design and development (34)(35)(36).…”

Section: Discussionmentioning

confidence: 99%

“…Reports on in vivo and in vitro applications of LPV in SARS treatment provided evidence that LPV and RTV may improve the Ribavarin effect on SARS infections in a dose dependent manner and reduce the death rate by about 20% -30% (43,44). Also, NFV, an anti HIV-1 protease, showed to prevent coronavirus replication and limit its cytotoxic effect on host cells (31)(32)(33)44). …”

mentioning

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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“…Another structural modification which has proven effective was the development of the fleximers – nucleoside analogues wherein the purine base has been split into two separate heterocyclic fragments but remains connected by a single C-C bond ( Seley et al, 2002 ; Seley et al, 2005 ; Peters H. et al, 2015 ; Ku and Seley-Radtke, 2018 ). Thus, the fleximers exhibit additional conformational freedom in order to maximize structural interactions in the active site of the target enzyme while maintaining the structural similarity with a normal nucleoside substrate or inhibitor necessary for recognition by the enzyme ( Seley et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

et al. 2022

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A new series of flexible 5′-norcarbocyclic aza/deaza-purine nucleoside analogs were synthesized from 6-oxybicyclo[3.1.0.]hex-2-ene and pyrazole-containing fleximer analogs of heterocyclic bases using the Trost procedure. The compounds were evaluated as potential inhibitors of E. coli purine nucleoside phosphorylase. Analog 1-3 were found to be noncompetitive inhibitors with inhibition constants of 14–24 mM. From the data obtained, it can be assumed that the new 5′-norcarbocyclic nucleoside analogs interact with the active site of the PNP like natural heterocyclic bases. But at the same time the presence of a cyclopentyl moiety with 2′ and 3′ hydroxyls is necessary for the inhibitory properties, since compounds 8–10, without those groups did not exhibit an inhibitory effect under the experimental conditions.

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Flexibility as a Strategy in Nucleoside Antiviral Drug Design

Cited by 15 publications

References 0 publications

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

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

Synthesis of New 5′-Norcarbocyclic Aza/Deaza Purine Fleximers - Noncompetitive Inhibitors of E.coli Purine Nucleoside Phosphorylase

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