Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

Hurwitz, Selwyn J.; Schinazi, Raymond F.

doi:10.1097/coh.0000000000000007

Cited by 11 publications

(12 citation statements)

References 55 publications

(50 reference statements)

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“…Furthermore, SAMHD1 has been investigated in the context of how cellular dNTP concentrations influence the efficacy of nucleoside reverse transcriptase inhibitors (NRTIs) for lentiviral infection [16–19]. Nucleoside derivatives–ribonucleoside, 2'-deoxyribonucleoside or arabinose nucleoside analogs–are antimetabolites, which represent an important class of chemotherapeutic agents used to treat cancers and viral infections [20–22]. These antimetabolites enter the cell through active transport mechanisms and require phosphorylation by several cellular kinases to produce their monophosphate (MP), diphosphate (DP) and triphosphate (TP) analog forms.…”

Section: Introductionmentioning

confidence: 99%

Substrates and Inhibitors of SAMHD1

Hollenbaugh¹,

Shelton²,

Tao³

et al. 2017

PLoS ONE

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SAMHD1 hydrolyzes 2'-deoxynucleoside-5'-triphosphates (dNTPs) into 2'-deoxynucleosides and inorganic triphosphate products. In this paper, we evaluated the impact of 2' sugar moiety substitution for different nucleotides on being substrates for SAMHD1 and mechanisms of actions for the results. We found that dNTPs ((2'R)-2'-H) are only permissive in the catalytic site of SAMHD1 due to L150 exclusion of (2'R)-2'-F and (2'R)-2'-OH nucleotides. However, arabinose ((2'S)-2'-OH) nucleoside-5'-triphosphates analogs are permissive to bind in the catalytic site and be hydrolyzed by SAMHD1. Moreover, when the (2'S)-2' sugar moiety is increased to a (2'S)-2'-methyl as with the SMDU-TP analog, we detect inhibition of SAMHD1’s dNTPase activity. Our computational modeling suggests that (2'S)-2'-methyl sugar moiety clashing with the Y374 of SAMHD1. We speculate that SMDU-TP mechanism of action requires that the analog first docks in the catalytic pocket of SAMHD1 but prevents the A351-V378 helix conformational change from being completed, which is needed before hydrolysis can occur. Collectively we have identified stereoselective 2' substitutions that reveal nucleotide substrate specificity for SAMHD1, and a novel inhibitory mechanism for the dNTPase activity of SAMHD1. Importantly, our data is beneficial for understanding if FDA-approved antiviral and anticancer nucleosides are hydrolyzed by SAMHD1 in vivo.

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Section: Introductionmentioning

confidence: 99%

Substrates and Inhibitors of SAMHD1

Hollenbaugh¹,

Shelton²,

Tao³

et al. 2017

PLoS ONE

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“…The in vivo potency of antiviral nucleoside agents is related to the pharmacokinetics of the agent, its cellular accumulation and phosphorylation to the active nucleotide triphosphate (NTP) form, the cellular stability of the NTP, and its binding affinity with the CMV polymerase target (14,15). The mean plasma concentrations (AUC 0 -24 /dose interval) between doses exceeded the in vitro 90% inhibitory concentration (IC 90 ) for doses of Ն100 mg per day (Fig.…”

Section: Discussionmentioning

confidence: 99%

Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

Rouphael

Hurwitz

Hart

et al. 2019

Antimicrob Agents Chemother

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Filociclovir (MBX-400, cyclopropavir) is an antiviral agent with activity against cytomegalovirus (CMV). A phase 1, double-blind, randomized, placebo-controlled (3:1 ratio), single-center, multiple-ascending-dose trial was conducted to assess the safety, tolerability, and pharmacokinetics of filociclovir. Filociclovir (n = 18) or placebo (n = 6) was administered as a daily oral dose (100 mg, 350 mg, or 750 mg) for 7 days to normal healthy adults (ages, 25 to 65 years) who were monitored for 22 days. Safety assessments included clinical, laboratory, and electrocardiogram monitoring. Plasma and urine samplings were used to determine pharmacokinetic parameters. All study product-related adverse events were mild, most commonly gastrointestinal (17%), nervous system (11%), and skin and subcutaneous tissue (11%) disorders. One subject had reversible grade 3 elevation in serum creatinine and bilirubin, which was associated with an ∼1-log increase in plasma filociclovir exposure compared to levels for other subjects in the same (750-mg) cohort. No other serious adverse events were observed. Plasma exposures (area under the concentration-time curve from 0 to 24 h [AUC0–24]) on days 1 and 7 were similar, suggesting negligible dose accumulation. There was a sublinear increase in plasma exposure with dose, which plateaued at the daily dose of 350 mg. The amount of filociclovir recovered in the urine remained proportional to plasma exposure (AUC). Doses as low as 100 mg achieved plasma concentrations sufficient to inhibit CMV in vitro. (This study has been registered at ClinicalTrials.gov under identifier NCT02454699.)

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“…However, these two enantiomers can suffer from limitations such as their reduced cell penetration (the free phosphonic acid form is negatively charged at physiological pH). Finally, we decided to synthesize the most commonly used carbonyloxymethyl pronucleotides (pivaloyloxymethylor POM) [13] prodrug forms of both enantiomers of compound 1. Indeed, the POM group, previously reported as a basic labile protecting group [14] does not introduce an additional stereochemical center at phosphorus atom.…”

Section: Chemistrymentioning

confidence: 99%

Discovery of an L‐like Configuration for 3’‐Fluoro‐5’‐norcarbonucleoside Phosphonates as Potent Anti‐HIV Agents

et al. 2022

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Recently, we reported the racemic synthesis of 3'-fluoro-5'norcarbocyclic nucleoside phosphonates bearing adenine as the heterocyclic base. For this study, to evaluate the antiviral activity of each enantiomer, we synthesized both enantiomers, as well as their corresponding bis(POM) prodrugs. Anti-HIV-1 evaluation against the LAI strain and clinically NRTI-resistant HIV-1 strains are presented. The activities against these different strains show that the activities of bis(POM) prodrug (À )-9 are equivalent or even superior to those of (R)-PMPA.

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Prodrug strategies for improved efficacy of nucleoside antiviral inhibitors

Cited by 11 publications

References 55 publications

Substrates and Inhibitors of SAMHD1

Substrates and Inhibitors of SAMHD1

Phase Ib Trial To Evaluate the Safety and Pharmacokinetics of Multiple Ascending Doses of Filociclovir (MBX-400, Cyclopropavir) in Healthy Volunteers

Discovery of an L‐like Configuration for 3’‐Fluoro‐5’‐norcarbonucleoside Phosphonates as Potent Anti‐HIV Agents

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