An efficient synthesis of RNA containing GS-441524: the nucleoside precursor of remdesivir

Moorthy, Ramkumar; Kennelly, Samantha A; Rodriguez, Deborah J.; Harki, Daniel A.

doi:10.1039/d1ra06589k

Cited by 3 publications

(2 citation statements)

References 38 publications

(20 reference statements)

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“…Adenosine 5′- O -(1-thiotriphosphate) (Sp isomer) was from BioLog. Remdesivir-terminated RNA was synthesized by both Dharmacon and the Harki lab as previously described ( 35 ). Remdesivir was provided to Dharmacon by Gilead Sciences, and this was chemically converted to the phosphoramidite to be synthetically incorporated into RNA.…”

Section: Methodsmentioning

confidence: 99%

Interfering with nucleotide excision by the coronavirus 3′-to-5′ exoribonuclease

Chinthapatla

Sotoudegan

Srivastava

et al. 2022

Nucleic Acids Research

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Some of the most efficacious antiviral therapeutics are ribonucleos(t)ide analogs. The presence of a 3′-to-5′ proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3′-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3′-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.

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Section: Methodsmentioning

confidence: 99%

Interfering with nucleotide excision by the coronavirus 3′-to-5′ exoribonuclease

Chinthapatla

Sotoudegan

Srivastava

et al. 2022

Nucleic Acids Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Adenosine 5'-O-(1-thiotriphosphate) (Sp isomer) was from BioLog. Remdesivir-terminated RNA was synthesized by both Dharmacon and the Harki lab as previously described (34). Remdesivir was provided to Dharmacon by Gilead Sciences, and this was chemically converted to the phosphoramidite to be synthetically incorporated into RNA.…”

Section: Methodsmentioning

confidence: 99%

Interfering with nucleotide excision by the coronavirus 3’-to-5’ exoribonuclease

Chinthapatla

Sotoudegan

Anderson

et al. 2022

Preprint

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Some of the most efficacious antiviral therapeutics are ribonucleos(t)ide analogs. The presence of a 3'-to-5' proofreading exoribonuclease (ExoN) in coronaviruses diminishes the potency of many ribonucleotide analogs. The ability to interfere with ExoN activity will create new possibilities for control of SARS-CoV-2 infection. ExoN is formed by a 1:1 complex of nsp14 and nsp10 proteins. We have purified and characterized ExoN using a robust, quantitative system that reveals determinants of specificity and efficiency of hydrolysis. Double-stranded RNA is preferred over single-stranded RNA. Nucleotide excision is distributive, with only one or two nucleotides hydrolyzed in a single binding event. The composition of the terminal basepair modulates excision. A stalled SARS-CoV-2 replicase in complex with either correctly or incorrectly terminated products prevents excision, suggesting that a mispaired end is insufficient to displace the replicase. Finally, we have discovered several modifications to the 3'-RNA terminus that interfere with or block ExoN-catalyzed excision. While a 3'-OH facilitates hydrolysis of a nucleotide with a normal ribose configuration, this substituent is not required for a nucleotide with a planar ribose configuration such as that present in the antiviral nucleotide produced by viperin. Design of ExoN-resistant, antiviral ribonucleotides should be feasible.

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Current Treatments for COVID-19: Application of Supercritical Fluids in the Manufacturing of Oral and Pulmonary Formulations

et al. 2022

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Even though more than two years have passed since the emergence of COVID-19, the research for novel or repositioned medicines from a natural source or chemically synthesized is still an unmet clinical need. In this review, the application of supercritical fluids to the development of novel or repurposed medicines for COVID-19 and their secondary bacterial complications will be discussed. We envision three main applications of the supercritical fluids in this field: (i) drug micronization, (ii) supercritical fluid extraction of bioactives and (iii) sterilization. The supercritical fluids micronization techniques can help to improve the aqueous solubility and oral bioavailability of drugs, and consequently, the need for lower doses to elicit the same pharmacological effects can result in the reduction in the dose administered and adverse effects. In addition, micronization between 1 and 5 µm can aid in the manufacturing of pulmonary formulations to target the drug directly to the lung. Supercritical fluids also have enormous potential in the extraction of natural bioactive compounds, which have shown remarkable efficacy against COVID-19. Finally, the successful application of supercritical fluids in the inactivation of viruses opens up an opportunity for their application in drug sterilization and in the healthcare field.

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An efficient synthesis of RNA containing GS-441524: the nucleoside precursor of remdesivir

Abstract: Remdesivir in RNA: An efficient synthesis of a GS-441524-containing phosphoramidite for solid-phase RNA synthesis is reported.

Cited by 3 publications

References 38 publications

Interfering with nucleotide excision by the coronavirus 3′-to-5′ exoribonuclease

Interfering with nucleotide excision by the coronavirus 3′-to-5′ exoribonuclease

Interfering with nucleotide excision by the coronavirus 3’-to-5’ exoribonuclease

Current Treatments for COVID-19: Application of Supercritical Fluids in the Manufacturing of Oral and Pulmonary Formulations

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