Advancement of prodrug approaches for nucleotide antiviral agents

2021 ◽  
Vol 21 ◽  
Author(s):  
Yanping Li ◽  
Bo Yang ◽  
Yanni Quan ◽  
Zhuorong Li
Keyword(s):  
Biological Activity ◽  
Active Metabolite ◽  
Antiviral Agents ◽  
Metabolic Activation ◽  
Significant Progress ◽  
Nucleotide Analogues ◽  
Lipophilic Prodrug ◽  
The Us ◽  
Intracellular Enzymes ◽  
Nucleoside Drugs

: Synthetic nucleoside or nucleotide analogues played a key role to the development of antiviral agents in past decades. However, low membrane permeability and insufficient cellular phosphorylation impaired the biological activity of polar nucleoside drugs because they have to penetrate the cell membrane and be phosphorylated to active metabolite in stepwise by intracellular enzymes. To overcome these limitations, diverse lipophilic prodrug modifications based on nucleoside mono-, di-, and triphosphate were designed and put into practice to efficiently deliver nucleoside into the target site, and bypass the rate-limited phosphorylation step. As the most successful prodrug strategy, ProTide technology has led to the discovery of three FDA-approved antiviral agents including sofosbuvir, tenofovir alafenadmide, and remdesivir which has been authorized for emergency use in patients of COVID-19 in the US. In recent years, nucleoside di- and triphosphate prodrugs have also made the significant progress. This review will focus on the summary of design approach and metabolic activation path of different nucleotide prodrug strategies. The potential application of nucleotide prodrugs for treatment of COVID-19 was also described due to the pandemic of SARS-CoV-2.

scholarly journals Effect of Genetic Variability in 20 Pharmacogenes on Concentrations of Tamoxifen and Its Metabolites

2021 ◽  
Vol 11 (6) ◽  
pp. 507
Author(s):  
Yuanhuang Chen ◽  
Lauren A. Marcath ◽  
Finn Magnus Eliassen ◽  
Tone Hoel Lende ◽  
Havard Soiland ◽  
...  
Keyword(s):  
Metabolic Activity ◽  
Active Metabolite ◽  
Estrogenic Activity ◽  
Metabolic Activation ◽  
Active Metabolites ◽  
Serum Samples ◽  
Concentration Data ◽  
Metabolism Pathway ◽  
Tamoxifen Metabolism ◽  
Tamoxifen Efficacy

Background: Tamoxifen, as a treatment of estrogen receptor positive (ER+) breast cancer, is a weak anti-estrogen that requires metabolic activation to form metabolites with higher anti-estrogenic activity. Endoxifen is the most-studied active tamoxifen metabolite, and endoxifen concentrations are highly associated with CYP2D6 activity. Associations of tamoxifen efficacy with measured or CYP2D6-predicted endoxifen concentrations have been inconclusive. Another active metabolite, 4-OHtam, and other, less active metabolites, Z-4′-endoxifen and Z-4′-OHtam, have also been reported to be associated with tamoxifen efficacy. Method: Genotype for 20 pharmacogenes was determined by VeriDose® Core Panel and VeriDose®CYP2D6 CNV Panel, followed by translation to metabolic activity phenotype following standard activity scoring. Concentrations of tamoxifen and seven metabolites were measured by UPLC-MS/MS in serum samples collected from patients receiving 20 mg tamoxifen per day. Metabolic activity was tested for association with tamoxifen and its metabolites using linear regression with adjustment for upstream metabolites to identify genes associated with each step in the tamoxifen metabolism pathway. Results: A total of 187 patients with genetic and tamoxifen concentration data were included in the analysis. CYP2D6 was the primary gene associated with the tamoxifen metabolism pathway, especially the conversion of tamoxifen to endoxifen. CYP3A4 and CYP2C9 were also responsible for the metabolism of tamoxifen. CYP2C9 especially impacted the hydroxylation to 4-OHtam, and this involved the OATP1B1 (SLCO1B1) transporter. Conclusion: Multiple genes are involved in tamoxifen metabolism and multi-gene panels could be useful to predict active metabolite concentrations and guide tamoxifen dosing.

scholarly journals Synthesis and Biological Activity of 1α,2α,25-Trihydroxyvitamin D3: Active Metabolite of 2α-(3-Hydroxypropoxy)-1α,25-dihydroxyvitamin D3 by Human CYP3A4

2014 ◽  
Vol 62 (2) ◽  
pp. 182-184 ◽  
Author(s):  
Masashi Takano ◽  
Saori Ohya ◽  
Kaori Yasuda ◽  
Miyu Nishikawa ◽  
Akiko Takeuchi ◽  
...  
Keyword(s):  
Biological Activity ◽  
Active Metabolite ◽  
Dihydroxyvitamin D3

ChemInform Abstract: A New Class of Acyclic Phosphonate Nucleotide Analogues: Phosphonate Isosters of Acyclovir and Ganciclovir Monophosphates as Antiviral Agents.

ChemInform ◽  
2010 ◽  
Vol 23 (2) ◽  
pp. no-no
Author(s):  
C. U. KIM ◽  
P. F. MISCO ◽  
B. Y. LUH ◽  
M. J. M. HITCHCOOK ◽  
I. GHAZZOULI ◽  
...  
Keyword(s):  
Antiviral Agents ◽  
Nucleotide Analogues ◽  
New Class

Triazene metabolism. III. In vitro cytotoxicity towards M21 cells and in vivo antitumour activity of the proposed metabolites of the antitumour 1-aryl-3,3-dimethyltriazenes

1984 ◽  
Vol 62 (4) ◽  
pp. 396-402 ◽  
Author(s):  
Douglas J. Kohlsmith ◽  
Keith Vaughan ◽  
Stephen J. Luner
Keyword(s):  
Cell Line ◽  
Chemical Stability ◽  
Active Metabolite ◽  
Melanoma Cell Line ◽  
Antitumour Activity ◽  
Metabolic Activation ◽  
In Vitro Cytotoxicity ◽  
Structural Analogues

In vitro cytotoxicity of a series of antitumour triazenes towards the M21 melanoma cell line has been studied. Dimethyltriazenes are structural analogues of 5-(3,3-dimethyl-1-triazeno-)imidazole-4-carboxamide (Dacarbazine) and are inactive, which is consistent with the requirement for metabolic activation. Monomethyltriazenes and hydroxymethyltriazenes, the proposed metabolites of the dimethyltriazenes, are cytotoxic to the M21 cell line. A new series of 4-hydroxy-1,2,3-benzotriazines has been tested for in vitro cytotoxicity. A series of monoalkyltriazenes (Ar∙N=N∙NHR) has been tested for antitumour activity against the P388 lymphoma in vivo. Only monomethyltriazenes had significant antitumour activity, which supports the hypothesis that the monomethyltriazene is the active metabolite of the antitumour dimethyltriazenes. The activity of monomethyltriazenes in vivo is correlated with the chemical stability and t1/2 measurements in pH 7.5 phosphate buffer.

scholarly journals The analysis of structure-anticancer and antiviral activity relationships for macrocyclic pyridinophanes and their analogues on the basis of 4D QSAR models (simplex representation of molecular structure).

2002 ◽  
Vol 49 (1) ◽  
pp. 157-168 ◽  
Author(s):  
Victor E Kuz'min ◽  
Anatoly G Artemenko ◽  
Victor P Lozitsky ◽  
Eugene N Muratov ◽  
Alla S Fedtchouk ◽  
...  
Keyword(s):  
Molecular Structure ◽  
Biological Activity ◽  
Antiviral Activity ◽  
Direct Synthesis ◽  
Antiviral Agents ◽  
Structural Models ◽  
Fourth Dimension ◽  
Molecular Fragments ◽  
Qsar Models ◽  
Fixed Structure

A new 4D-QSAR approach has been considered. For all investigated molecules the 3D structural models have been created and the set of conformers (fourth dimension) have been used. Each conformer is represented as a system of different simplexes (tetratomic fragments of fixed structure, chirality and symmetry). The investigation of influence of molecular structure of macrocyclic pyridinophanes, their analogues and certain other compounds on anticancer and antiviral (anti-influenza, antiherpes and antiadenovirus) activity has been carried out by means of the 4D-QSAR. Statistic characteristics for QSAR of PLS (partial least squares) models are satisfactory (R = 0.92-0.97; CVR = 0.63-0.83). Molecular fragments increasing and decreasing biological activity were defined. This information may be useful for design, and direct synthesis of novel anticancer and antiviral agents.

scholarly journals MODERN ETHIOTROPIC CHEMOTHERAPY OF HERPESVIRUS INFECTIONS: ADVANCES, NEW TRENDS AND PERSPECTIVES. ALPHAHERPESVIRINAE (part I)

2018 ◽  
Vol 63 (3) ◽  
pp. 106-114
Author(s):  
V. L. Andronova
Keyword(s):  
Drug Resistance ◽  
Biological Activity ◽  
Dna Polymerase ◽  
Antiviral Agents ◽  
Structural Features ◽  
Modern Medicine ◽  
Antiviral Drugs ◽  
Modified Nucleosides ◽  
Herpesvirus Infection ◽  
New Compounds

Modern therapy of infections caused by alpha-herpesviruses is based on drugs belonging to the class of modified nucleosides (acyclovir) and their metabolic progenitors - valine ester of acyclovir and famciclovir (prodrug of penciclovir). The biological activity of these compounds is determined by the similarity of their structure to natural nucleosides: modified nucleosides compete with natural nucleosides for binding to DNA-polymerase and, due to their structural features, inhibit its activity. However, the emergence of variants of viruses resistant to the antiviral drugs available in the arsenal of modern medicine necessitates the search for new compounds able of effectively inhibiting the reproduction of viruses. These compounds should be harmless to the macroorganisms, convenient to use, and overcoming the drug resistance barrier in viruses. The search for literature in international databases (PubMed, MedLine, RINC, etc.) in order to obtain information on promising developments that open new possibilities for treating herpesvirus infection and subsequent analysis of the collected data made it possible to determine not only the main trends in the search for new antiviral agents, but also to provide information on the compounds most promising for the development of anti-herpesvirus drugs.

scholarly journals The patent analysis features of different purpose radar systems with using the resources of the US Patent and Trademark Office.

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
V.I. Karnyshev ◽  
◽  
V.I. Avdzeiko ◽  
E.S. Pascal ◽  
◽  
...  
Keyword(s):  
Information Sources ◽  
Systems Development ◽  
Radio Waves ◽  
International Patent Classification ◽  
Significant Progress ◽  
Practical Applications ◽  
Patent Classification ◽  
Radar Systems ◽  
International Patent ◽  
The Us

The patent documentation is one of the main information sources for forecasting the development of various technical (technological) areas. This paper examines the features of radar systems development with the use of the US Patent and Trademark Office resources. In this study, the data concerning the dynamics of USA invention patents registration for ten-year period (2010-2019) have been found for G01S13 (“Radar systems”) group of the International Patent Classification. The results obtained confirm the significant progress achieved in the development of the systems using the reflection or reradiation of radio waves in specific practical applications. In particular, the inventions intended for using in space (“space”), airspace (“air”), as well as in ground and surface (“surface”) systems. It is shown that during the last ten years the systems using reflection of radio waves (“primary radar systems”) and radar systems, specially adapted for specific applications, have demonstrated the best dynamics in their development. As a result of the data analysis, it is concluded that the radar systems, specially adapted for such specific applications as anti-collision purposes, radar systems for such specific applications, and primary radar systems, should be considered as the most promising in the next two to three years.

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