Nucleotide Analogues as Antiviral Agents, Copyright, ACS Symposium Series, Foreword

: 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.

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Nucleotide Analogues as Antiviral Agents

10.1021/bk-1989-0401 ◽

1989 ◽

Cited By ~ 20

Keyword(s):

Antiviral Agents ◽

Nucleotide Analogues

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ChemInform Abstract: Synthesis of 2′-Aminomethyl Derivatives of N-(2-(Phosphonomethoxy) ethyl) Nucleotide Analogues as Potential Antiviral Agents.

ChemInform ◽

10.1002/chin.199649250 ◽

2010 ◽

Vol 27 (49) ◽

pp. no-no

Author(s):

H. DVORAKOVA ◽

M. MASOJIDKOVA ◽

A. HOLY ◽

J. BALZARINI ◽

G. ANDREI ◽

...

Keyword(s):

Antiviral Agents ◽

Nucleotide Analogues ◽

Aminomethyl Derivatives ◽

Derivatives Of

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Synthesis of 2‘-Aminomethyl Derivatives ofN-(2-(Phosphonomethoxy)ethyl) Nucleotide Analogues as Potential Antiviral Agents

Journal of Medicinal Chemistry ◽

10.1021/jm9601314 ◽

1996 ◽

Vol 39 (17) ◽

pp. 3263-3268 ◽

Cited By ~ 12

Author(s):

Hana Dvořáková ◽

Milena Masojídková ◽

Antonín Holý ◽

Jan Balzarini ◽

Graciela Andrei ◽

...

Keyword(s):

Antiviral Agents ◽

Nucleotide Analogues ◽

Aminomethyl Derivatives

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Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday

Molecules ◽

10.3390/molecules26040923 ◽

2021 ◽

Vol 26 (4) ◽

pp. 923 ◽

Cited By ~ 2

Author(s):

Guangdi Li ◽

Tingting Yue ◽

Pan Zhang ◽

Weijie Gu ◽

Ling-Jie Gao ◽

...

Keyword(s):

Infectious Diseases ◽

Tenofovir Disoproxil Fumarate ◽

Adefovir Dipivoxil ◽

Antiviral Agents ◽

Emerging Infectious Diseases ◽

Hiv Infections ◽

80Th Birthday ◽

Nucleotide Analogues ◽

Varicella Zoster ◽

Tenofovir Alafenamide

Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread®) and tenofovir alafenamide (Vemlidy®) against HIV and HBV infections and adefovir dipivoxil (Hepsera®) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex®) against HSV-1 and VZV infections and stavudine (Zerit®) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex®, Zelitrex®) against HSV and VZV and rabacfosadine (Tanovea®-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide®) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.

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