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Viruses Apr 2021The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute... (Review)
Review
The emergence or re-emergence of viruses with epidemic and/or pandemic potential, such as Ebola, Zika, Middle East Respiratory Syndrome (MERS-CoV), Severe Acute Respiratory Syndrome Coronavirus 1 and 2 (SARS and SARS-CoV-2) viruses, or new strains of influenza represents significant human health threats due to the absence of available treatments. Vaccines represent a key answer to control these viruses. However, in the case of a public health emergency, vaccine development, safety, and partial efficacy concerns may hinder their prompt deployment. Thus, developing broad-spectrum antiviral molecules for a fast response is essential to face an outbreak crisis as well as for bioweapon countermeasures. So far, broad-spectrum antivirals include two main categories: the family of drugs targeting the host-cell machinery essential for virus infection and replication, and the family of drugs directly targeting viruses. Among the molecules directly targeting viruses, nucleoside analogues form an essential class of broad-spectrum antiviral drugs. In this review, we will discuss the interest for broad-spectrum antiviral strategies and their limitations, with an emphasis on virus-targeted, broad-spectrum, antiviral nucleoside analogues and their mechanisms of action.
Topics: Adenosine Monophosphate; Alanine; Amides; Animals; Antiviral Agents; Hemorrhagic Fever, Ebola; Humans; Middle East Respiratory Syndrome Coronavirus; Mutagenesis; Nucleosides; Pyrazines; Ribavirin; SARS-CoV-2; Virus Replication; Zika Virus; Zika Virus Infection; COVID-19 Drug Treatment
PubMed: 33924302
DOI: 10.3390/v13040667 -
Journal of Feline Medicine and Surgery Apr 2019The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for cats suffering from various forms of naturally acquired feline...
OBJECTIVES
The aim of this study was to determine the safety and efficacy of the nucleoside analog GS-441524 for cats suffering from various forms of naturally acquired feline infectious peritonitis (FIP).
METHODS
Cats ranged from 3.4-73 months of age (mean 13.6 months); 26 had effusive or dry-to-effusive FIP and five had non-effusive disease. Cats with severe neurological and ocular FIP were not recruited. The group was started on GS-441524 at a dosage of 2.0 mg/kg SC q24h for at least 12 weeks and increased when indicated to 4.0 mg/kg SC q24h.
RESULTS
Four of the 31 cats that presented with severe disease died or were euthanized within 2-5 days and a fifth cat after 26 days. The 26 remaining cats completed the planned 12 weeks or more of treatment. Eighteen of these 26 cats remain healthy at the time of publication (OnlineFirst, February 2019) after one round of treatment, while eight others suffered disease relapses within 3-84 days. Six of the relapses were non-neurological and two neurological. Three of the eight relapsing cats were treated again at the same dosage, while five cats had the dosage increased from 2.0 to 4.0 mg/kg q24h. The five cats treated a second time at the higher dosage, including one with neurological disease, responded well and also remain healthy at the time of publication. However, one of the three cats re-treated at the original lower dosage relapsed with neurological disease and was euthanized, while the two remaining cats responded favorably but relapsed a second time. These two cats were successfully treated a third time at the higher dosage, producing 25 long-time survivors. One of the 25 successfully treated cats was subsequently euthanized due to presumably unrelated heart disease, while 24 remain healthy.
CONCLUSIONS AND RELEVANCE
GS-441524 was shown to be a safe and effective treatment for FIP. The optimum dosage was found to be 4.0 mg/kg SC q24h for at least 12 weeks.
Topics: Animals; Cats; Feline Infectious Peritonitis; Female; Male; Nucleosides
PubMed: 30755068
DOI: 10.1177/1098612X19825701 -
Molecules (Basel, Switzerland) Mar 2020For decades, nucleosides and nucleotides have formed the cornerstone of antiviral, antiparasitic and anticancer therapeutics and have been used as tools in exploring...
For decades, nucleosides and nucleotides have formed the cornerstone of antiviral, antiparasitic and anticancer therapeutics and have been used as tools in exploring nucleic acid structure and function [...].
Topics: Anti-Bacterial Agents; Antiprotozoal Agents; Antiviral Agents; Computational Biology; Humans; Nucleic Acids; Nucleosides; Nucleotides
PubMed: 32230805
DOI: 10.3390/molecules25071526 -
Veterinary Microbiology Jun 2018Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in...
Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies of diseases caused by several RNA viruses in people and other species indicate that antiviral therapy may be effective against FIP in cats. The small molecule nucleoside analog GS-441524 is a molecular precursor to a pharmacologically active nucleoside triphosphate molecule. These analogs act as an alternative substrate and RNA-chain terminator of viral RNA dependent RNA polymerase. We determined that GS-441524 was non-toxic in feline cells at concentrations as high as 100 uM and effectively inhibited FIPV replication in cultured CRFK cells and in naturally infected feline peritoneal macrophages at concentrations as low as 1 uM. We determined the pharmacokinetics of GS-441524 in cats in vivo and established a dosage that would sustain effective blood levels for 24 h. In an experimental FIPV infection of cats, GS-441524 treatment caused a rapid reversal of disease signs and return to normality with as little as two weeks of treatment in 10/10 cats and with no apparent toxicity.
Topics: Animals; Antiviral Agents; Ascitic Fluid; Cats; Cells, Cultured; Coronavirus Infections; Coronavirus, Feline; Feline Infectious Peritonitis; Macrophages; Nucleosides; Serogroup; Virus Replication
PubMed: 29778200
DOI: 10.1016/j.vetmic.2018.04.026 -
Antiviral Chemistry & Chemotherapy 2018
Topics: Antiviral Agents; Dose-Response Relationship, Drug; Humans; Microbial Sensitivity Tests; Molecular Structure; Nucleosides; Prodrugs; Structure-Activity Relationship; Viruses
PubMed: 29890841
DOI: 10.1177/2040206618781410 -
Drug Discovery Today Jul 2022With several US Food and Drug Administration (FDA)-approved drugs and high barriers to resistance, nucleoside and nucleotide analogs remain the cornerstone of antiviral... (Review)
Review
With several US Food and Drug Administration (FDA)-approved drugs and high barriers to resistance, nucleoside and nucleotide analogs remain the cornerstone of antiviral therapies for not only herpesviruses, but also HIV and hepatitis viruses (B and C); however, with the exception of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for which vaccines have been developed at unprecedented speed, there are no vaccines or small antivirals yet available for (re)emerging viruses, which are primarily RNA viruses. Thus, herein, we present an overview of ribonucleoside analogs recently developed and acting as inhibitors of the viral RNA-dependent RNA polymerase (RdRp). They are new lead structures that will be exploited for the discovery of new antiviral nucleosides.
Topics: Antiviral Agents; Humans; Nucleosides; RNA-Dependent RNA Polymerase; United States
PubMed: 35189369
DOI: 10.1016/j.drudis.2022.02.013 -
Journal of Medicinal Chemistry Mar 2018The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this... (Review)
Review
The ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates. In this approach, the hydroxyls of the monophosphate or monophosphonate groups are masked by an aromatic group and an amino acid ester moiety, which are enzymatically cleaved-off inside cells to release the free nucleoside monophosphate and monophosphonate species. Structurally, this represents the current end-point of an extensive medicinal chemistry endeavor that spans almost three decades. It started from the masking of nucleoside monophosphate and monophosphonate groups by simple alkyl groups and evolved into the sophisticated ProTide system as known today. This technology has been extensively employed in drug discovery, and it has already led to the discovery of two FDA-approved (antiviral) ProTides. In this work, we will review the development of the ProTide technology, its application in drug discovery, and its role in the improvement of drug delivery and efficacy.
Topics: Animals; Chemistry, Pharmaceutical; Humans; Nucleosides; Prodrugs; Structure-Activity Relationship
PubMed: 28792763
DOI: 10.1021/acs.jmedchem.7b00734 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Jun 2023Nucleoside drugs play an essential role in treating major diseases such as tumor and viral infections, and have been widely applied in clinics. However, the... (Review)
Review
Nucleoside drugs play an essential role in treating major diseases such as tumor and viral infections, and have been widely applied in clinics. However, the effectiveness and application of nucleoside drugs are significantly limited by their intrinsic properties such as low bioavailability, lack of targeting ability, and inability to enter the cells. Nanocarriers can improve the physiological properties of nucleoside drugs by improving drug delivery efficiency and availability, maintaining drug efficacy and system stability, adjusting the binding ability of the carrier and drug molecules, as well as modifying specific molecules to achieve active targeting. Starting from the design strategy of nucleoside drug nanodelivery systems, the design and therapeutic effect of these nanomedicines are described in this review, and the future development directions of nucleoside/nucleotide-loaded nanomedicines are also discussed.
Topics: Nanomedicine; Nucleosides; Nucleotides; Nanoparticles; Drug Delivery Systems; Drug Carriers
PubMed: 37476939
DOI: 10.3724/zdxbyxb-2022-0701 -
Postepy Biochemii Jun 2022Nucleoside boranephosphonates are nucleotide analogues in which one of the non-bridging oxygen atom of the phosphate part has been replaced by a borane group (-BH3).... (Review)
Review
Nucleoside boranephosphonates are nucleotide analogues in which one of the non-bridging oxygen atom of the phosphate part has been replaced by a borane group (-BH3). This modification imparts a wide spectrum of biological activity, e.g., activation of ribonuclease H, resistance to endo- and exonucleases, and their respective triphosphates are good substrates for DNA and RNA polymerases. Nucleoside boranephosphonate derivatives are used in antisense therapy, silencing gene expression using siRNA strategies, and as potential antiviral and anti-cancer prodrugs. Boranephosphonates find also applications as aptamers and as substrates in a new method of DNA sequencing. This review briefly presents potential biological applications of nucleoside boranephosphonates.
Topics: Antiviral Agents; DNA; Nucleosides; Nucleotides; Sequence Analysis, DNA
PubMed: 35792645
DOI: 10.18388/pb.2021_425 -
Chemical Reviews May 2021Nucleosides play central roles in all facets of life, from metabolism to cellular signaling. Because of their physiochemical properties, nucleosides are lipid bilayer... (Review)
Review
Nucleosides play central roles in all facets of life, from metabolism to cellular signaling. Because of their physiochemical properties, nucleosides are lipid bilayer impermeable and thus rely on dedicated transport systems to cross biological membranes. In humans, two unrelated protein families mediate nucleoside membrane transport: the concentrative and equilibrative nucleoside transporter families. The objective of this review is to provide a broad outlook on the current status of nucleoside transport research. We will discuss the role played by nucleoside transporters in human health and disease, with emphasis placed on recent structural advancements that have revealed detailed molecular principles of these important cellular transport systems and exploitable pharmacological features.
Topics: Biological Transport, Active; Humans; Models, Molecular; Nucleoside Transport Proteins; Nucleosides; Protein Conformation; Substrate Specificity
PubMed: 33232132
DOI: 10.1021/acs.chemrev.0c00644