Diversification of Nucleoside Analogues as Potent Antiviral Drug Leads

Nucleoside analogues are potent antiviral agents, but the continuous emergence of pathogenic viruses demands novel and diverse structures. Herein, we have created a diversified library of highly bioactive and non-cytotoxic nucleoside analogues featuring an unprecedented carbobicyclic core that mimics natural ribonucleoside conformation. These regio- and stereo-divergent analogues exhibit up to 16-fold greater antiviral efficacy than the FDA-approved antiviral, ribavirin. Importantly, the carbobicyclic core structure is critical for the potent antiviral efficacy, thus opening up ample opportunities for further lead optimization and mechanistic investigations.

[1]  Michal Hocek,et al.  Synthesis of Polycyclic Hetero-Fused 7-Deazapurine Heterocycles and Nucleosides through C–H Dibenzothiophenation and Negishi Coupling , 2022, Journal of the American Chemical Society.

[2]  Scott J. Miller,et al.  Chemoselective Acylation of Nucleosides , 2022, Chemistry.

[3]  S. Madhi,et al.  Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis , 2022, The Lancet.

[4]  P. Herdewijn,et al.  An Overview of Marketed Nucleoside and Nucleotide Analogs , 2022, Current protocols.

[5]  Yahiya Y. Syed.  Molnupiravir: First Approval , 2022, Drugs.

[6]  Emily M. Lee,et al.  Pyrimidine inhibitors synergize with nucleoside analogues to block SARS-CoV-2 , 2022, Nature.

[7]  K. Jacobson,et al.  Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets. , 2021, RSC medicinal chemistry.

[8]  Parthasarathi Das,et al.  Short Synthesis of Molnupiravir (EIDD-2801) via a Thionated Uridine Intermediate , 2021, ACS omega.

[9]  C. Dienemann,et al.  Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis , 2021, Nature Structural & Molecular Biology.

[10]  Aiping Lu,et al.  ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties , 2021, Nucleic Acids Res..

[11]  E. Anderson,et al.  The Future of Respiratory Syncytial Virus Disease Prevention and Treatment , 2021, Infectious Diseases and Therapy.

[12]  Jiayun Zhang,et al.  RNA-dependent RNA polymerase (RdRp) inhibitors: The current landscape and repurposing for the COVID-19 pandemic , 2021, European Journal of Medicinal Chemistry.

[13]  Yvette N. Lamb.  Remdesivir: First Approval , 2020, Drugs.

[14]  Xiaohua Ma,et al.  Molecular Insights into Small Molecule Drug Discovery for SARS-CoV-2. , 2020, Angewandte Chemie.

[15]  M. Hall,et al.  Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19 , 2020, ACS central science.

[16]  Anton C. de Groot.  Abacavir , 2020, Reactions Weekly.

[17]  S. Madhi,et al.  Causes of severe pneumonia requiring hospital admission in children without HIV infection from Africa and Asia: the PERCH multi-country case-control study , 2019, The Lancet.

[18]  K. Jacobson,et al.  Design and in Vivo Characterization of A1 Adenosine Receptor Agonists in the Native Ribose and Conformationally Constrained (N)-Methanocarba Series. , 2019, Journal of medicinal chemistry.

[19]  K. Seley‐Radtke,et al.  The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold , 2018, Antiviral Research.

[20]  Wai-Lung Ng,et al.  Synthetic and Biological Studies of Carbasugar SGLT2 Inhibitors , 2018, Journal of Synthetic Organic Chemistry, Japan.

[21]  Katherine L. Seley‐Radtke,et al.  The evolution of nucleoside analogue antivirals: A review for chemists and non-chemists. Part 1: Early structural modifications to the nucleoside scaffold , 2018, Antiviral Research.

[22]  Xiaojuan Wang,et al.  Crystal structure and Hirshfeld surface analysis of the anhydrous form of the nucleoside analogue entecavir. , 2018, Acta crystallographica. Section C, Structural chemistry.

[23]  F. Wang,et al.  Total Synthesis of Entecavir: A Robust Route for Pilot Production , 2018 .

[24]  C. Lau,et al.  Palladium-Catalyzed Arylation of Carbasugars Enables the Discovery of Potent and Selective SGLT2 Inhibitors. , 2016, Angewandte Chemie.

[25]  William A. Lee,et al.  Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys , 2016, Nature.

[26]  P. Lam,et al.  Synthesis of Biologically Active Piperidine Metabolites of Clopidogrel: Determination of Structure and Analyte Development. , 2015, The Journal of organic chemistry.

[27]  P. Chan,et al.  Conformationally locked bicyclo[4.3.0]nonane carbanucleosides: synthesis and bio-evaluation. , 2014, Organic & biomolecular chemistry.

[28]  S. C. Pellegrinet,et al.  Diels–Alder reactions of pinacol alkenylboronates: an experimental and theoretical study , 2014 .

[29]  C. Lau,et al.  Design, syntheses, and SAR studies of carbocyclic analogues of sergliflozin as potent sodium-dependent glucose cotransporter 2 inhibitors. , 2013, Angewandte Chemie.

[30]  Fabien Zoulim,et al.  Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases , 2013, Nature Reviews Drug Discovery.

[31]  S. C. Pellegrinet,et al.  Theoretical investigation of the Diels-Alder reactions of unsaturated boronates. , 2013, Organic & biomolecular chemistry.

[32]  John A. Tallarico,et al.  Identification of broad-spectrum antiviral compounds and assessment of the druggability of their target for efficacy against respiratory syncytial virus (RSV) , 2011, Proceedings of the National Academy of Sciences.

[33]  O. Arjona,et al.  Synthesis and conformational and biological aspects of carbasugars. , 2007, Chemical reviews.

[34]  T. Carell,et al.  Synthesis of the transfer-RNA nucleoside queuosine by using a chiral allyl azide intermediate. , 2007, Angewandte Chemie.

[35]  S. Hughes,et al.  The history of N-methanocarbathymidine: the investigation of a conformational concept leads to the discovery of a potent and selective nucleoside antiviral agent. , 2006, Antiviral research.

[36]  C. Meier,et al.  Influence of the N3‐Protection Group on N1‐ vs. O2‐Alkylation in the Mitsunobu Reaction , 2006 .

[37]  C. K. Chu,et al.  Synthesis of cyclopentenyl carbocyclic nucleosides as potential antiviral agents against orthopoxviruses and SARS. , 2006, Journal of medicinal chemistry.

[38]  G. Hilt,et al.  Boron‐Substituted Building Blocks in Diels—Alder and Other Cycloaddition Reactions. , 2005 .

[39]  T. Snape,et al.  Synthesis and Revision of the Stereochemistry of a Cyclopentenone Natural Product Isolated from Ascomycete Strain A23-98. , 2004 .

[40]  H. Moon,et al.  Synthesis of fluorinated cyclopentenyladenine as potent inhibitor of S-adenosylhomocysteine hydrolase. , 2004, Bioorganic & medicinal chemistry letters.

[41]  M. Tunçbilek,et al.  5′-Nor Carbocyclic Ribavirin , 2003, Nucleosides, nucleotides & nucleic acids.

[42]  H. Rhee,et al.  Synthesis of Carbocyclic 1-[4-(Hydroxymethyl)cyclopent-2-enyl]-1,2,4-triazole-3-carboxamide and Its Derivatives , 2003, Nucleosides, nucleotides & nucleic acids.

[43]  A. McPhail,et al.  Enantioselective syntheses of carbocyclic ribavirin and its analogs: Linear versus convergent approaches , 2000 .

[44]  K. Squires.  An Introduction to Nucleoside and Nucleotide Analogues , 2000, Antiviral therapy.

[45]  O. Kocy,et al.  BMS-200475, a novel carbocyclic 2′-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro , 1997 .

[46]  K. Altmann,et al.  4′,6′-Methano carbocyclic thymidine: A conformationally constrained building block for oligonucleotides , 1994 .

[47]  C. Broome,et al.  Use of Ribavirin in the Treatment of Respiratory Syncytial Virus Infection , 1993, Pediatrics.

[48]  R. Schinazi,et al.  Activities of the four optical isomers of 2',3'-dideoxy-3'-thiacytidine (BCH-189) against human immunodeficiency virus type 1 in human lymphocytes , 1992, Antimicrobial Agents and Chemotherapy.

[49]  M. Wainberg,et al.  Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2'-deoxy-3'-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog , 1991, Antimicrobial Agents and Chemotherapy.

[50]  G. Chmurny,et al.  Preparation and Antiviral Activity of Several Deoxygenated Ribavirin and Tiazofurin Derivatives , 1990 .

[51]  E. De Clercq,et al.  Antiviral activity of phosphonylmethoxyalkyl derivatives of purine and pyrimidines. , 1987, Antiviral research.

[52]  D W Barry,et al.  3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[53]  J. Jiricny,et al.  The benzoylation of uracil and thymine , 1984 .

[54]  D. Heermann,et al.  GLYCOSYLHYDRAZINES. 4. 1H-1,2,4-TRIAZOLE NUCLEOSIDES - SYNTHESIS OF VIRAZOLE , 1981 .

[55]  J. Descamps,et al.  SYNTHESIS AND DETERMINATION OF ANTIVIRAL ACTIVITY OF THE 2′(3′)-O-METHYL DERIVATIVES OF RIBAVIRIN (1-β-D-RIBOFURANOSYL-1,2,4-TRIAZOLE-3-CARBOXAMIDE) , 1978 .

[56]  M. Sundaralingam,et al.  The crystal and molecular structures of two polymorphic crystalline forms of virazole (1-β-d-ribofuranosyl-1,2,4-triazole-3-carboxamide). A new synthetic broad sprectrum antiviral agent , 1976 .

[57]  M. Sundaralingam,et al.  Conformational analysis of the sugar ring in nucleosides and nucleotides. A new description using the concept of pseudorotation. , 1972, Journal of the American Chemical Society.

[58]  R. K. Robins,et al.  Design, synthesis, and broad spectrum antiviral activity of 1-.beta.-D-ribofuranosyl-1,2,4-triazole-3-carboxamide and related nucleosides , 1972 .

[59]  R. Wagner,et al.  Nucleosides with a twist. Can fixed forms of sugar ring pucker influence biological activity in nucleosides and oligonucleotides? , 1996, Journal of Medicinal Chemistry.

[60]  A. Holý,et al.  Synthesis of 9-(2-Phosphinomethoxyethyl)adenine and Related Compounds , 1987 .