Inhibitors of Nucleotide Biosynthesis As Candidates for a Wide Spectrum of Antiviral Chemotherapy

Overview

Journal Microorganisms

Specialty Microbiology

Date 2022 Aug 26

PMID 36014049

Authors

Claudia Soledad Sepulveda

Cybele Carina Garcia

Elsa Beatriz Damonte

Affiliations

Soon will be listed here.

Abstract

Emerging and re-emerging viruses have been a challenge in public health in recent decades. Host-targeted antivirals (HTA) directed at cellular molecules or pathways involved in virus multiplication represent an interesting strategy to combat viruses presently lacking effective chemotherapy. HTA could provide a wide range of agents with inhibitory activity against current and future viruses that share similar host requirements and reduce the possible selection of antiviral-resistant variants. Nucleotide metabolism is one of the more exploited host metabolic pathways as a potential antiviral target for several human viruses. This review focuses on the antiviral properties of the inhibitors of pyrimidine and purine nucleotide biosynthesis, with an emphasis on the rate-limiting enzymes dihydroorotate dehydrogenase (DHODH) and inosine monophosphate dehydrogenase (IMPDH) for which there are old and new drugs active against a broad spectrum of pathogenic viruses.

Citing Articles

Bovine Serum Albumin Nanoparticle-Mediated Delivery of Ribavirin and Mycophenolic Acid for Enhanced Antiviral Therapeutics.

Castaneda Catana M, Rivas Marquina A, Dodes Traian M, Carlucci M, Damonte E, Perez O Viruses. 2025; 17(2).

PMID: 40006893 PMC: 11860702. DOI: 10.3390/v17020138.

Multi-omics analysis reveals the impact of influenza a virus host adaptation on immune signatures in pig tracheal tissue.

Laybourn H, Hellemann Polhaus C, Kristensen C, Lyngfeldt Henriksen B, Zhang Y, Brogaard L Front Immunol. 2024; 15:1432743.

PMID: 39247193 PMC: 11378526. DOI: 10.3389/fimmu.2024.1432743.

Antiviral Potential of Azathioprine and Its Derivative 6- Mercaptopurine: A Narrative Literature Review.

Rios-Usuga C, Martinez-Gutierrez M, Ruiz-Saenz J Pharmaceuticals (Basel). 2024; 17(2).

PMID: 38399389 PMC: 10892228. DOI: 10.3390/ph17020174.

Metabolic Enzymes in Viral Infection and Host Innate Immunity.

Qin C, Xie T, Yeh W, Savas A, Feng P Viruses. 2024; 16(1).

PMID: 38257735 PMC: 10820379. DOI: 10.3390/v16010035.

Metabolomics analysis of the effect of acidification on rhizosphere soil microecosystem of tea tree.

Ye J, Wang Y, Lin S, Wang Y, Chen P, Hong L Front Plant Sci. 2023; 14:1137465.

PMID: 36909384 PMC: 9998672. DOI: 10.3389/fpls.2023.1137465.

References

Luthra P, Naidoo J, Pietzsch C, De S, Khadka S, Anantpadma M . Inhibiting pyrimidine biosynthesis impairs Ebola virus replication through depletion of nucleoside pools and activation of innate immune responses. Antiviral Res. 2018; 158:288-302. PMC: 6436837. DOI: 10.1016/j.antiviral.2018.08.012. View

Sanders S, Harisdangkul V . Leflunomide for the treatment of rheumatoid arthritis and autoimmunity. Am J Med Sci. 2002; 323(4):190-3. DOI: 10.1097/00000441-200204000-00004. View

Wang W, Cui J, Ma H, Lu W, Huang J . Targeting Pyrimidine Metabolism in the Era of Precision Cancer Medicine. Front Oncol. 2021; 11:684961. PMC: 8194085. DOI: 10.3389/fonc.2021.684961. View

Liacini A, Seamone M, Muruve D, Tibbles L . Anti-BK virus mechanisms of sirolimus and leflunomide alone and in combination: toward a new therapy for BK virus infection. Transplantation. 2010; 90(12):1450-7. DOI: 10.1097/TP.0b013e3182007be2. View

Holmes E, Pehlke D, Kelley W . Human IMP dehydrogenase. Kinetics and regulatory properties. Biochim Biophys Acta. 1974; 364(2):209-17. DOI: 10.1016/0005-2744(74)90006-0. View

Buey R, Ledesma-Amaro R, Velazquez-Campoy A, Balsera M, Chagoyen M, de Pereda J . Guanine nucleotide binding to the Bateman domain mediates the allosteric inhibition of eukaryotic IMP dehydrogenases. Nat Commun. 2015; 6:8923. PMC: 4660370. DOI: 10.1038/ncomms9923. View

Di Virgilio F, Adinolfi E . Extracellular purines, purinergic receptors and tumor growth. Oncogene. 2016; 36(3):293-303. PMC: 5269532. DOI: 10.1038/onc.2016.206. View

Guarner J . Three Emerging Coronaviruses in Two Decades. Am J Clin Pathol. 2020; 153(4):420-421. PMC: 7109697. DOI: 10.1093/ajcp/aqaa029. View

Shigeta S, Mori S, Baba M, Ito M, Honzumi K, Nakamura K . Antiviral activities of ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide, and 6'-(R)-6'-C-methylneplanocin A against several ortho- and paramyxoviruses. Antimicrob Agents Chemother. 1992; 36(2):435-9. PMC: 188453. DOI: 10.1128/AAC.36.2.435. View

10.

Wang Y, Zhou X, Debing Y, Chen K, van der Laan L, Neyts J . Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology. 2014; 146(7):1775-83. DOI: 10.1053/j.gastro.2014.02.036. View

11.

Kumarasamy D, Roy B, Rocha-Pereira J, Neyts J, Nanjappan S, Maity S . Synthesis and in vitro antiviral evaluation of 4-substituted 3,4-dihydropyrimidinones. Bioorg Med Chem Lett. 2016; 27(2):139-142. PMC: 7127791. DOI: 10.1016/j.bmcl.2016.12.010. View

12.

Hosoya M, Shigeta S, Ishii T, Suzuki H, De Clercq E . Comparative inhibitory effects of various nucleoside and nonnucleoside analogues on replication of influenza virus types A and B in vitro and in ovo. J Infect Dis. 1993; 168(3):641-6. DOI: 10.1093/infdis/168.3.641. View

13.

Rustgi V, Lee W, Lawitz E, Gordon S, Afdhal N, Poordad F . Merimepodib, pegylated interferon, and ribavirin in genotype 1 chronic hepatitis C pegylated interferon and ribavirin nonresponders. Hepatology. 2009; 50(6):1719-26. DOI: 10.1002/hep.23204. View

14.

Juvale K, Shaik A, Kirubakaran S . Inhibitors of inosine 5'-monophosphate dehydrogenase as emerging new generation antimicrobial agents. Medchemcomm. 2019; 10(8):1290-1301. PMC: 6727467. DOI: 10.1039/c9md00179d. View

15.

Pancheva S . Potentiating effect of ribavirin on the anti-herpes activity of acyclovir. Antiviral Res. 1991; 16(2):151-61. DOI: 10.1016/0166-3542(91)90021-i. View

16.

Salam A, Cheng V, Edwards T, Olliaro P, Sterne J, Horby P . Time to reconsider the role of ribavirin in Lassa fever. PLoS Negl Trop Dis. 2021; 15(7):e0009522. PMC: 8266111. DOI: 10.1371/journal.pntd.0009522. View

17.

Park J, Avila-Perez G, Nogales A, Blanco-Lobo P, de la Torre J, Martinez-Sobrido L . Identification and Characterization of Novel Compounds with Broad-Spectrum Antiviral Activity against Influenza A and B Viruses. J Virol. 2020; 94(7). PMC: 7081893. DOI: 10.1128/JVI.02149-19. View

18.

Zhang D, Sun W, Zhong Z, Gao R, Yi H, Li Y . Synthesis and broad-spectrum antiviral activity of some novel benzo-heterocyclic amine compounds. Molecules. 2014; 19(1):925-39. PMC: 6271935. DOI: 10.3390/molecules19010925. View

19.

Madak J, Bankhead 3rd A, Cuthbertson C, Showalter H, Neamati N . Revisiting the role of dihydroorotate dehydrogenase as a therapeutic target for cancer. Pharmacol Ther. 2018; 195:111-131. DOI: 10.1016/j.pharmthera.2018.10.012. View

20.

Cao L, Weetall M, Trotta C, Cintron K, Ma J, Kim M . Targeting of Hematologic Malignancies with PTC299, A Novel Potent Inhibitor of Dihydroorotate Dehydrogenase with Favorable Pharmaceutical Properties. Mol Cancer Ther. 2018; 18(1):3-16. PMC: 6318026. DOI: 10.1158/1535-7163.MCT-18-0863. View