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Emerging and reemerging viruses pose significant public health threats, underscoring the urgent need for new antiviral drugs. Recently, a novel family of antiviral acyclic nucleoside phosphonates (ANP) composed of a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl phosphonic acid skeleton (O-DAPy nucleobase) has shown promise. Among these, LAVR-289 stands out for its potent inhibitory effects against various DNA viruses. Despite its efficacy, LAVR-289s poor water solubility hampers effective drug delivery. To address this, innovative delivery systems utilizing lipidic derivatives have been explored for various administration routes. Submicron lyotropic liquid crystals (LLCs) are particularly promising drug carriers for the encapsulation, protection, and delivery of lipophilic drugs like LAVR-289. This study focuses on developing submicron-sized lipid mesophase dispersions, including emulsified L 2 phase, cubosomes, and hexosomes, by adjusting lipidic compounds such as Dimodan® U/J, Lecithins E80, and Miglyol® 812 N. These formulations aim to enhance the solubility and bioavailability of LAVR-289. In vitro evaluations demonstrated that LAVR-289-loaded LLCs at a concentration of 1 µM efficiently inhibited vaccinia virus in infected human cells, with no observed cytotoxicity. Notably, hexosomes exhibited the most favorable antiviral outcomes, suggesting that the internal mesophase structure plays a critical role in optimizing the therapeutic efficacy of this drug class., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: ‘Luigi A. Agrofoglio reports financial support was provided by French National Research Agency. Luigi A. Agrofoglio reports was provided by National Institutes of Health. Luigi A. Agrofoglio reports was provided by Centre-Val de Loire Region. Franck Gallardo and Elie Marcheteau are shareholder and employee of NeoVirTech, respectively. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

New acyclic pyrimidine nucleoside phosphonate prodrugs with a 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid skeleton (O-DAPy nucleobase) were prepared through a convergent synthesis by olefin cross-metathesis as the key step. Several acyclic nucleoside 4-(2,4-diaminopyrimidin-6-yl)oxy-but-2-enyl]phosphonic acid prodrug exhibited in vitro antiviral activity in submicromolar or nanomolar range against varicella zoster virus (VZV), human cytomegalovirus (HCMV), human herpes virus type 1 (HSV-1) and type 2 (HSV-2), and vaccinia virus (VV), with good selective index (SI). Among them, the analogue 9c (LAVR-289) proved markedly inhibitory against VZV wild-type (TK+) (EC 50 0.0035 μM, SI 740) and for thymidine kinase VZV deficient strains (EC 50 0.018 μM, SI 145), with a low morphological toxicity in cell culture at 100 μM and acceptable cytostatic activity resulting in excellent selectivity. Compound 9c exhibited antiviral activity against HCMV (EC 50 0.021 μM) and VV (EC 50 0.050 μM), as well as against HSV-1 (TK-) (EC 50 0.0085 μM). Finally, LAVR-289 (9c) deserves further (pre)clinical investigations as a potent candidate broad-spectrum anti-herpesvirus drug., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Nucleoside analogues are at the forefront of antiviral therapy for last decades. To circumvent some of their limitations, based on their metabolism, and in order to improve their anti-viral potency and selectivity, several families of nucleoside analogues have been described through structural modifications at the sugar and heterocycles. The replacement of the oxygen of the nucleoside by a methylene has led to the family of carbocyclic (or cyclopentane) nucleoside analogues. Various potent anti-HIV and anti-HBV drugs belong to this family. Main syntheses of carbocyclic analogues of nucleosides used Diels-Alder reactions (in racemic or asymmetric series), but also started from carbohydrates (ribose, glucose), as a source of optically active compounds, which then had to be transformed into carbacycles under various conditions. The growing interest in carbocyclic nucleosides has led several groups, including ours, to develop new analogues and to explore novel routes. This article will review some of the recent chemistry developed on selected five-membered ring carbocyclic nucleosides., (© 2022 The Chemical Society of Japan & Wiley-VCH GmbH.)

Novel 2-substituted-6-[(4-substituted-1-piperidyl)methyl]-1H-benzimidazoles were designed and synthesized as Ebola virus inhibitors. The proposed structures of the new prepared benzimidazole-piperidine hybrids were confirmed based on their spectral data and CHN analyses. The target compounds were screened in vitro for their anti-Ebola activity. Among tested molecules, compounds 26a (EC 50= 0.93 μM, SI = 10) and 25a (EC 50= 0.64 μM, SI = 20) were as potent as and more selective than Toremifene reference drug (EC 50  = 0.38 μM, SI = 7) against cell line. Data suggests that the mechanism by which 25a and 26a block EBOV infection is through the inhibition of viral entry at the level of NPC1. Furthermore, a docking study revealed that several of the NPC1 amino acids that participate in binding to GP are involved in the binding of the most active compounds 25a and 26a. Finally, in silico ADME prediction indicates that 26a is an idealy drug-like candidate. Our results could enable the development of small molecule drug capable of inhibiting Ebola virus, especially at the viral entry step., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

A series of hitherto unknown (1,4-disubstituted-1,2,3-triazol)-( E )-2-methyl-but-2-enyl nucleosides phosphonate prodrugs bearing 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as the key synthetic step. All novel compounds were evaluated for their antiviral activities against HBV, HIV and SARS-CoV-2. Among these molecules, only compound 15j , a hexadecyloxypropyl (HDP)/( isopropyloxycarbonyl -oxymethyl)-ester (POC) prodrug, showed activity against HBV in Huh7 cell cultures with 62% inhibition at 10 μM, without significant cytotoxicity (IC 50 = 66.4 μM in HepG2 cells, IC 50 = 43.1 μM in HepG2 cells) at 10 μM.

Several hitherto unknown (E)-but-2-enyl nucleoside phosphonoamidate analogs (ANPs) were prepared directed with nitrogen reagents by cross-metathesis in water-under ultrasound irradiation. Two diastereoisomers were formally identified by X-ray diffraction. These compounds were evaluated against a large spectrum of DNA and RNA viruses. Among them, the phosphonoamidate thymine analogue 19 emerged as the best prodrug against varicella-zoster virus (VZV) with EC 50 values of 0.33 and 0.39 μM for wild-type and thymidine kinase deficient strains, respectively, and a selectivity index ≥200 μM. This breakthrough approach paves the way for new purine and pyrimidine (E)-but-2-enyl phosphonoamidate analogs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The synthesis and evaluation against various cysteine cathepsins with endopeptidase activity, of two new families of hitherto unknown 1,3,5-triazines, substituted by a nitrile function and either a cyclohexylamine moiety (5-like) or a piperazine moiety (9-like) are described. The structure-activity relationship was discussed; from 16 synthesized novel compounds, 9h was the most active and selectively inhibitor of Cat K (IC50 = 28 nM) and Cat S (IC50 = 23 nM). Molecular docking of 9h to X-ray crystal structure of cathepsins K and S confirmed a common binding mode with a crucial covalent bond with Cys25. We observed for 9h that p-trifluorophenyl group is located in S2 pocket and possess hydrophobic interactions with Tyr67 and Met68. Triazine and piperazine moieties are located in S'1 pocket and interact with Gly23, Cys63, Gly64 and Gly65. Altogether, these results indicate that the new analogs can make them effective agents against some viruses for which the glycoprotein cleavage is mediated by an array of proteases., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Nucleoside analogs are extremely useful for the development of therapeutic agents to control viral diseases and cancer. Among the numerous modifications on the nucleoside skeleton, replacement of the oxygen of the furanose ring by a CH2 group resulted in increased flexibility and higher resistance to phosphorylases and led to carbocyclic nucleoside analogs (or carbanucleosides). The broad spectrum of biological activities of carbocyclic nucleosides led to tremendous research interest in their syntheses. The article documents recent strategies for the synthesis of active carbocyclic nucleosides by presenting individual case studies, such as the neplanocins, entecavir and selected fluorinated carbocyclic nucleosides. Furthermore, it provides new insights into new directions for more potent and active carbocyclic nucleoside analogs.

A series of seventeen hitherto unknown ANP analogs bearing the (E)-but-2-enyl aliphatic side chain and modified heterocyclic base such as cytosine and 5-fluorocytosine, 2-pyrazinecarboxamide, 1,2,4-triazole-3-carboxamide or 4-substituted-1,2,3-triazoles were prepared in a straight approach through an olefin acyclic cross metathesis as key synthetic step. All novel compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex virus type 1 and 2, varicella zoster virus, feline herpes virus, human cytomegalovirus, hepatitis C virus (HCV), HIV-1 and HIV-2. Among these molecules, only compound 31 showed activity against human cytomegalovirus in HEL cell cultures with at EC50 of ∼10 μM. Compounds 8a, 13, 14, and 24 demonstrated pronounced anti-HCV activity without significant cytotoxicity at 100 μM., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Seventeen hitherto unknown bis(POM) prodrugs of novel (E)-[4'-phosphono-but-2'-en-1'-yl]purine nucleosides were prepared in a straight approach and at good yields. Those compounds were synthesized by the reaction of purine nucleobases directly with the phosphonate synthon 3 bearing POM biolabile groups under Mitsunobu conditions. All obtained compounds were evaluated for their antiviral activities against a large number of DNA and RNA viruses including herpes simplex viruses 1 and 2, varicella zoster virus, Feline herpes virus, human cytomegalovirus, HIV-1 and HIV-2. Among these molecules, some of them exhibit anti-VZV and anti-HIV activity at submicromolar concentrations. This class of compound will be of further interest for lead optimization as anti-infectious agents., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Starting from acetylated 5-ethynyl-2'-deoxyuridine (3), 14 hitherto unknown C5-substituted-(1,3-diyne)-2'-deoxyuridines (with cyclopropyl, hydroxymethyl, methylcyclopentane, p-(substituted)phenyl and disubstituted-phenyl substituents) have been synthesized via a nickel-copper catalyzed C-H activation between two terminal alkynes, in yields ranging from 19% to 67%. Their antiviral activities were measured against a large number of DNA and RNA viruses including herpes simplex virus type 1 and type 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. The 5-[4-(4-trifluoromethoxyphenyl)buta-1,3-diynyl]-2'-deoxyuridine (26) is the most potent inhibitor of this series against VZV with an EC(50) of ~1 μM and a CC(50) of 55 μM. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including influenza virus A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and vesicular stomatitis, coxsackie B4 and respiratory syncytial virus in HeLa cell cultures and against human immunodeficiency virus type 1 and 2 in CEM cell cultures, with no specific antiviral effect. This class of compounds could be of further interest for lead optimization as anti-infectious (i.e. herpetic) agents., (Copyright © 2012. Published by Elsevier Masson SAS.)

The synthesis and antiviral evaluation of a series of C5-(1,4- and 1,5-disubstituted-1,2,3-triazolo)-nucleoside derivatives is described. The key steps of this synthesis are regioselective Huisgen's 1,3-dipolar cycloaddition, using either copper-catalyzed azide-alkyne cycloaddition (CuAAC) or ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) under microwave activation. Some compounds among the 5a-l series possess activity against herpes simplex viruses 1 and 2, varicella-zoster virus, human cytomegalovirus and vaccinia virus. Their cytostatic activities were determined against murine leukemia cells, human T-lymphocyte cells and cervix carcinoma cells. Compounds were also evaluated on a wide panel of RNA viruses, including Vesicular stomatitis virus, influenza viruses type A (H1N1 and H3N2) and B in MDCK cell cultures, parainfluenza-3 virus, reovirus-1, Sindbis virus and Punta Toro virus in Vero cell cultures and Vesicular stomatitis, Coxsackie B4 and respiratory syncytial virus, with no specific antiviral effect., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies. They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases. New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase. Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate-cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovir. Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP. The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC(50) = 3 μM) and against varicella zoster virus in vitro (IC(50) = 0.19 μM), in contrast to the corresponding inactive (Z) derivatives. Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates.

Antiviral nucleoside and nucleotide analogs, essential for the treatment of viral infections in the absence of efficient vaccines, are prodrug forms of the active compounds that target the viral DNA polymerase or reverse transcriptase. The activation process requires several successive phosphorylation steps catalyzed by different kinases, which are present in the host cell or encoded by some of the viruses. These activation reactions often are rate-limiting steps and are thus open to improvement. We review here the structural and enzymatic properties of the enzymes that carry out the activation of analogs used in therapy against human immunodeficiency virus and against DNA viruses such as hepatitis B, herpes and poxviruses. Four major classes of drugs are considered: thymidine analogs, non-natural L-nucleosides, acyclic nucleoside analogs and acyclic nucleoside phosphonate analogs. Their efficiency as drugs depends both on the low specificity of the viral polymerase that allows their incorporation into DNA, but also on the ability of human/viral kinases to provide the activated triphosphate active forms at a high concentration at the right place. Two distinct modes of action are considered, depending on the origin of the kinase (human or viral). If the human kinases are house-keeping enzymes that belong to the metabolic salvage pathway, herpes and poxviruses encode for related enzymes. The structures, substrate specificities and catalytic properties of each of these kinases are discussed in relation to drug activation., (Copyright 2010 Elsevier B.V. All rights reserved.)

In recent decades, nucleosides analogs have been the cornerstone in the treatment of various diseases, such as AIDS, herpes and hepatitis. More than 40 modified nucleosides are officially approved by the US FDA and represent the major compound class for inhibition of viral replication. By comparison with traditional conditions, microwave irradiation offers a powerful tool that can increase yields and decrease reaction time, with simple manipulation and an environmentally friendly way. Here, we report the latest progress in nucleoside synthesis using microwave irradiation.

Unlike most DNA viruses, poxviruses replicate in the cytoplasm of host cells. They encode enzymes needed for genome replication and transcription, including their own thymidine and thymidylate kinases. Some herpes viruses encode only 1 enzyme catalyzing both reactions, a peculiarity used for prodrug activation to obtain maximum specificity. We have solved the crystal structures of vaccinia virus thymidylate kinase bound to TDP or brivudin monophosphate. Although the viral and human enzymes have similar sequences (42% identity), they differ in their homodimeric association and active-site geometry. The vaccinia TMP kinase dimer arrangement is orthogonal and not antiparallel as in human enzyme. This different monomer orientation is related to the presence of a canal connecting the edge of the dimer interface to the TMP base binding pocket. Consequently, the pox enzyme accommodates nucleotides with bulkier bases, like brivudin monophosphate and dGMP; these are efficiently phosphorylated and stabilize the enzyme. The brivudin monophosphate-bound structure explains the structural basis for this specificity, opening the way to the rational development of specific antipox agents that may also be suitable for poxvirus TMP kinase gene-based chemotherapy of cancer.

Hitherto unknown 1,4-disubstituted-[1,2,3]-triazolo-4',4'-dihydroxymethyl-3'-deoxy carbanucleosides were synthesized based on a "click approach." Various alkynes were introduced on a key azido intermediate by the "click" 1,3-dipolar Huisgen cycloaddition. Their antiviral activities and cellular toxicities were evaluated on vaccinia virus. None of the synthesized compounds exhibited a significant antiviral activity.

With the commercial availability of well-defined ruthenium metathesis catalysts which combine high stability and broad functional group compatibility, olefin metathesis is now routinely integrated in various syntheses. We will report here the overwhelming power and scope of cross-metathesis in the area of new acyclic nucleoside phosphonates. Scope and limitations of this approach, and especially the E/Z stereocontrol, are discussed on selected examples from our drug discovery group.

In this article, we report the synthesis of hitherto unknown 5-haloethynyl and 5-(1,2-dihalo)vinyluracil nucleosides in the 2'-deoxy, 3'-deoxy- and ribosyl series, and we discuss their in vitro anti-HIV and anti-HCV activities and cellular toxicitites. As a result, on the basis of their selectivity index (SI) obtained with the HCV replicon system, but also on their cytotoxicity on peripheral blood mononuclear, CEM and VERO cell lines, the best compounds were the 5-bromoethynyluridine (SI = 3.2) and the 5-(1-chloro-2-iodo)vinyluridine (SI > 2.8).

The synthesis of novel acyclic nucleosides in the 5-alkynyl and 6-alkylfuro[2,3-d]pyrimidine series is described. These compounds were evaluated against HIV and HSV in order to determine their spectrum of antiviral activity. Their cytotoxicities against PBM, CEM and VERO cells were also determined. Compounds 21d and 24b displayed moderate EC50s of 2.7 and 4.9 microM, respectively, against HIV-1 and of 6.3 and 4.8 microM, respectively, against HSV. Nevertheless, these compounds also showed cellular toxicity, suggesting that the antiviral effects are secondary to the toxic effects.

The success of the early nucleoside agents, the toxicity and metabolic instability of many nucleoside analogues and the effects of viral pathogens on public health are driving the design, synthesis and evaluation of new nucleoside analogues. In this context, a powerful reaction has emerged over the past decade that has fundamentally changed the outlook on nucleoside chemistry: the olefin metathesis reaction. This review is designed to give an overview of the synthesis of some nucleosides of biological interest, according to their structural types (e.g., neplanocins and aristeromycin analogues, 2',3'-unsaturated nucleoside analogues, and acyclonucleosides), using metathesis reactions by employing either the alkoxy imido molybdenum catalyst developed by Schrock and various ruthenium carbene catalysts developed by Grubbs, Hoveyda-Grubbs and Nolan.

The synthesis of carbocyclic and phosphonocarbocyclic analogues of ribavirin, an anti-HCV inhibitor, are described. Those compounds were evaluated against HCV but also against other important viruses in order to determine their spectrum of antiviral activity. Compounds 6 and 13 displayed a moderate IC(50) against HIV-1 of 43.8 and 37 microM, respectively.

The article presents a study which reviews previous literatures to describe the strategies used in making cyclonucleosides. It notes that the discovery of natural nucleosides from marine sponges was vital for the development of antileukemic Ara-C and antiviral agents Ara-A. It mentions that nucleosides application in chemotherapy and the recognition of stereo- or regioselective organic reactions can be made possible for the development of synthetic nucleosides with antiviral properties.

The synthesis and antiviral evaluation of a series of dihydropyrimidinone and thiopyrimidine derivatives bearing aryl α,γ-diketobutanoic acid moiety are described using the Biginelli multicomponent reaction as key step. The most active among 20 synthesized novel compounds were 4c, 4d and 5b, which possess nanomolar HIV-1 integrase (IN) stand transfer (ST) inhibition activities. In order to understand their mode of interactions within the IN active site, we docked all the compounds into the previously reported X-ray crystal structure of IN. We observed that compounds 4c , 4d and 5b occupied an area close to the two catalytic Mg 2+ ions surrounded by their chelating triad (E221, D128 and D185), DC16, Y212 and the β -diketo acid moiety of 4c , 4d and 5b chelating Mg 2+ . As those compounds lack anti-HIV activities in cell, their prodrugs were synthetized. The prodrug 4c ′ exhibited an anti-HIV activity of 0.19 μM in primary human lymphocytes with some cytotoxicity. All together, these results indicate that the new analogs potentially interact within the catalytic site with highly conserved residues important for IN catalytic activity. [ABSTRACT FROM AUTHOR]

Abstract: The pathogenic mycoplasma Ureaplasma parvum (Up) causes opportunistic infections and relies on salvage of nucleosides for DNA synthesis and Up thymidine kinase (UpTK) provides the necessary thymidine nucleotides. The anti-HIV compound 3´-azido-3′-deoxythymidine (AZT) is a good substrate for TK. Methods for a rapid and efficient synthesis of new 3′-α-[1,2,3]triazol-3′-deoxythymidine analogs from AZT under Huisgen conditions are described. Thirteen 3′-analogues were tested with human cytosolic thymidine kinase (hTK1) and UpTK. The new analogs showed higher efficiencies (K m/V max values) in all cases with UpTK than with hTK1. Still, hTK1 was preferentially inhibited by 9 out of 10 tested analogs. Structural models of UpTK and hTK1 were constructed and used to explain the kinetic results. Two different binding modes of the nucleosides within the active sites of both enzymes were suggested with one predominating in the bacterial enzyme and the other in hTK1. These results will aid future development of anti-mycoplasma nucleosides. [Copyright &y& Elsevier]

Abstract: Vaccinia virus thymidylate kinase, although similar in sequence to human TMP kinase, has broader substrate specificity and phosphorylates (E)-5-(2-bromovinyl)-dUMP and dGMP. Modified guanines such as glyoxal-dG, 8-oxo-dG, O6-methyl-dG, N2-ethyl-dG and N7-methyl-dG were found present in cancer cell DNA. Alkylated and oxidized dGMP analogs were examined as potential substrates for vaccinia TMP kinase and also for human TMP and GMP kinases. Molecular models obtained from structure-based docking rationalized the enzymatic data. All tested nucleotides are found surprisingly substrates of vaccinia TMP kinase and also of human GMP kinase. Interestingly, O6-methyl-dGMP is the only analog specific for the vaccinia enzyme. Thus, O6-Me-dGMP could be useful for designing new compounds of medical interest either in antipoxvirus therapy or in experimental combined gene/chemotherapy of cancer. These results also provide new insights regarding dGMP analog reaction with human GMP kinase and their slow recycling by salvage pathway nucleotide kinases. [Copyright &y& Elsevier]