Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2′-C-methyl-6-O-methyl guanosine nucleoside and l-Alanine ester phosphoramidates

Bourdin, Claire; McGuigan, Christopher; Brancale, Andrea; Chamberlain, Stanley D.; Vernachio, John; Hutchins, Jeff; Gorovits, Elena L.; Kolykhalov, Alexander A.; Muhammad, Jerry; Patti, Joseph M.; Henson, Geoffrey; Bleiman, Blair; Bryant, K. Dawn; Ganguly, Babita; Hunley, Damound; Obikhod, Aleksandr; Walters, C. Robin; Wang, Jin; Ramamurty, Changalvala V. S.; Battina, Srinivas K.; Rao, Chenghao

doi:10.1016/j.bmcl.2012.12.004

Cited by 4 publications

(6 citation statements)

References 16 publications

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“…204 In sofosbuvir, for example, the 5'-monophosphate form of the nucleoside analogue is masked as an aryloxy phosphoramidate triester ( Figure 6) and those masking groups are cleaved intracellularly via a cascade mechanism that is initiated by host carboxypeptidase or -esterase. [205][206][207] This type of phosphoramidate pronucleotide ('ProTide'), pioneered by Chris McGuigan and colleagues (for a review see Mehellou et al 208 ), was designed to release (non-natural) nucleoside monophosphates inside cells. The same technology is also used in remdesivir and while sofosbuvir specifically targets HCV, remdesivir has gained attention as potential anti-Ebola virus and, importantly, anti-coronavirus treatment.…”

Section: Problems Of Virus-targeted Nucleoside Analogues In Antiviralmentioning

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: Problems Of Virus-targeted Nucleoside Analogues In Antiviralmentioning

confidence: 99%

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

Huchting

2020

Antivir Chem Chemother

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“…64,125 In these preliminary investigations, the metabolism of d4T phosphoramidates with pig liver carboxylesterase (CES) was studied 125 using in situ 31 P NMR analysis, a technique following that is now routinely employed in McGuigan’s laboratories as a predictive tool for the likely in vitro biological activity as well as for SAR establishment. The original protocol of this enzymatic experiment was later adapted to study the ProTide first activation step with carboxypeptidase Y enzyme, to prove the nucleoside monophosphate release in biological matrix such as cell lysate 126 or to test the prodrug stability in human serum. 76…”

Section: Metabolic Activation Pathwaymentioning

confidence: 99%

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Ślusarczyk

Serpi

Pertusati

2018

Antivir Chem Chemother

105

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Following the first report on the nucleoside phosphoramidate (ProTide) prodrug approach in 1990 by Chris McGuigan, the extensive investigation of ProTide technology has begun in many laboratories. Designed with aim to overcome limitations and the key resistance mechanisms associated with nucleoside analogues used in the clinic (poor cellular uptake, poor conversion to the 5'-monophosphate form), the ProTide approach has been successfully applied to a vast number of nucleoside analogues with antiviral and anticancer activity. ProTides consist of a 5'-nucleoside monophosphate in which the two hydroxyl groups are masked with an amino acid ester and an aryloxy component which once in the cell is enzymatically metabolized to deliver free 5'-monophosphate, which is further transformed to the active 5'-triphosphate form of the nucleoside analogue. In this review, the seminal contribution of Chris McGuigan's research to this field is presented. His technology proved to be extremely successful in drug discovery and has led to two Food and Drug Administration-approved antiviral agents.

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“…For instance, 7‐deaza‐2′‐ C ‐methylguanosine 61 was shown to be completely inactive . Even its prodrug, 6‐ O ‐methyl derivative 62 that should be more lipophilic and therefore should enter the cells more easily, is devoid of any anti‐HCV activity . Also phosphate prodrug approach failed to bring promising anti‐HCV compounds as the prodrugs were poorly active and/or cytotoxic .…”

Section: Nucleosides With Antiviral Activitiesmentioning

confidence: 99%

“…Even its prodrug, 6‐ O ‐methyl derivative 62 that should be more lipophilic and therefore should enter the cells more easily, is devoid of any anti‐HCV activity . Also phosphate prodrug approach failed to bring promising anti‐HCV compounds as the prodrugs were poorly active and/or cytotoxic . Also other sugar‐modified 7‐deazaguanine nucleosides, such as 2′‐ O ‐methylribonucleoside 63a and 3′‐deoxyribonucleoside 63b were strong HCV RNA polymerase inhibitors as NTPs but again their phosphate prodrugs were only weakly active or inactive …”

Section: Nucleosides With Antiviral Activitiesmentioning

confidence: 99%

“…118 Also phosphate prodrug approach failed to bring promising anti-HCV compounds as the prodrugs were poorly active and/or cytotoxic. 118 Also other sugar-modified 7-deazaguanine nucleosides, such as 2 ′ -O-methylribonucleoside 63a and 3 ′ -deoxyribonucleoside 63b were strong HCV RNA polymerase inhibitors as NTPs 111,119 but again their phosphate prodrugs were only weakly active or inactive. 119 7-Hetaryl-7-deaza-2 ′ -C-methyladenosines generally show modest (micromolar) anti-HCV activities 46,120,121 ( Fig.…”

Section: F I G U R E 1mentioning

confidence: 99%

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Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

Perlíková

Hocek

2017

Medicinal Research Reviews

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Abstract7‐Deazapurine (pyrrolo[2,3‐d]pyrimidine) nucleosides are important analogues of biogenic purine nucleosides with diverse biological activities. Replacement of the N7 atom with a carbon atom makes the five‐membered ring more electron rich and brings a possibility of attaching additional substituents at the C7 position. This often leads to derivatives with increased base‐pairing in DNA or RNA or better binding to enzymes. Several types of 7‐deazapurine nucleosides with potent cytostatic or cytotoxic effects have been identified. The most promising are 7‐hetaryl‐7‐deazaadenosines, which are activated in cancer cells by phosphorylation and get incorporated both to RNA (causing inhibition of proteosynthesis) and to DNA (causing DNA damage). Mechanism of action of other types of cytostatic nucleosides, 6‐hetaryl‐7‐deazapurine and thieno‐fused deazapurine ribonucleosides, is not yet known. Many 7‐deazaadenosine derivatives are potent inhibitors of adenosine kinases. Many types of sugar‐modified derivatives of 7‐deazapurine nucleosides are also strong antivirals. Most important are 2′‐C‐methylribo‐ or 2′‐C‐methyl‐2′‐fluororibonucleosides with anti‐HCV activities (several compounds underwent clinical trials). Some underexplored areas of potential interest are also outlined.

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Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2′-C-methyl-6-O-methyl guanosine nucleoside and l-Alanine ester phosphoramidates

Cited by 4 publications

References 16 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

Phosphoramidates and phosphonamidates (ProTides) with antiviral activity

Pyrrolo[2,3‐d]pyrimidine (7‐deazapurine) as a privileged scaffold in design of antitumor and antiviral nucleosides

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