Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity

Yates, Mary K.; Chatterjee, Payel; Flint, Mike; Arefeayne, Yafet; Makuc, Damjan; Plavec, Janez; Spiropoulou, Christina F.; Seley‐Radtke, Katherine L.

doi:10.3390/molecules24173184

Cited by 14 publications

(8 citation statements)

References 24 publications

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“… 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 . 184 – 186 Still, the mechanism of action remains subject of studies and although it has been shown that fleximer-triphosphates can be substrates for nucleic acid polymerases, 187 it is still unclear whether the antiviral activity of acyclic fleximers is achieved via this mechanism. Mutagenic properties similar to ribavirin etc.…”

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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“…L-carnitine plays an essential role in the production of energy and fatty acid metabolism. This can further improve and control the immune-modulatory functions in diabetic patients, neuropathic pain, and other liver and kidney-related diseases [66,67]. Thus, carnitine could be a good option to prevent the harm caused by COVID-19.…”

Section: Importance Of Dietary Supplementsmentioning

confidence: 99%

A Rapid Advice Guideline for the Prevention of Novel Coronavirus Through Nutritional Intervention

2020

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Purpose of Review An unexpected and sudden outbreak of a novel infection known as a coronavirus (COVID-19) has imposed important problems to global well-being and economy. Based upon current researches, this virus is spreading from one human to another through respiratory droplets, i.e. cough and sneeze. Till now, there has not been any specific treatment found for this virus. Hence, there is a critical need to discover alternative techniques to cope with the current scenario. Recent Findings This review conducted an online search for prevention of coronavirus infection with the help of nutritional interventions. It has been observed that the effect of the virus is mostly on the individual with low immunity, individual affected with diseases like diabetes, and individual using any immune-suppressed drug or having past history of major surgeries or severe medical conditions. Summary Therefore, consuming foods which boost immunity helps in preventing respiratory-related disorder or suppressing diseases-related problems, which could be helpful in controlling the spread of this virus. In conclusion, it has been suggested that before the beginning of generalised treatments and interventions in each infected patient, nutritional status should be evaluated, as it can help in creating a specific nutrition intervention for the infected individual.

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“…Commercially available DNA polymerases were used: endonuclease-free A detailed study by Seley-Radtke and coworkers revealed the relationships between the structure of functionalized pyrimidine ring and the activity of imidazole-pyrimidine fleximers against the Ebola virus, as well as mentioned some unpublished data on antiflavivirus properties of the "classic" fleximers. 24 The correlation between the biological properties and structural features of "flexible" nucleobases was discussed in a monograph published in 2014. 28 Acyclic bitriazole nucleosides 24 (Scheme 10) exhibited antiproliferative activity against the drug-resistant pancreatic cancer cell line MIA PaCa-2, which is associated with caspase-dependent apoptosis.…”

Section: The Biological Activity Of Fleximersmentioning

confidence: 99%

“… 22 This could, for example, explain the unexpected earlier observation: fleximer guanosine analog 2 inhibited S- adenosyl- L-homocysteine hydrolase (EC 3.3.1.1) – an enzyme that is specific for adenosine, while fleximer 1 (an adenosine analog) did not interact with this enzyme. 23 Both ribosides and acyclic fleximers 24 predominantly existed in their anti conformations in solutions (compounds 35 – 38 , Fig. 1 ).…”

mentioning

confidence: 99%

“…A detailed study by Seley-Radtke and coworkers revealed the relationships between the structure of functionalized pyrimidine ring and the activity of imidazole-pyrimidine fleximers against the Ebola virus, as well as mentioned some unpublished data on antiflavivirus properties of the "classic" fleximers. 24 The correlation between the biological properties and structural features of "flexible" nucleobases was discussed in a monograph published in 2014. 28…”

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confidence: 99%

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Nucleoside Analogs with Fleximer Nucleobase

Chudinov

2020

Chem Heterocycl Comp

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This review article is devoted to the so-called fleximer nucleoside analogs, containing two or more planar moieties in the heterocyclic base, connected by a bond that permits rotation. Such analogs have been proposed as molecular probes for detecting enzyme-substrate interactions and studying the transcription and translation of nucleic acids, but subsequently have attracted the interest of researchers by their antiviral and antitumor activity. The methods used in the synthesis of such compounds, along with their structural features and also biological activity are considered in this review.

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Probing the Effects of Pyrimidine Functional Group Switches on Acyclic Fleximer Analogues for Antiviral Activity

Cited by 14 publications

References 24 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

A Rapid Advice Guideline for the Prevention of Novel Coronavirus Through Nutritional Intervention

Nucleoside Analogs with Fleximer Nucleobase

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