Helicases As Antiviral Drug Targets

Overview

Journal Drug News Perspect

Publisher Thomson Reuters

Specialty Pharmacology

Date 2003 Sep 16

PMID 12973446

Citations 36

Authors

David N Frick

Affiliations

Soon will be listed here.

Abstract

Helicases catalytically unwind duplex DNA or RNA using energy derived from the hydrolysis of nucleoside triphosphates and are attractive drug targets because they are required for viral replication. This review discusses methods for helicase identification, classification and analysis, and presents an overview of helicases that are necessary for the replication of human pathogenic viruses. Newly developed methods to analyze helicases, coupled with recently determined atomic structures, have led to a better understanding of their mechanisms of action. The majority of this research has concentrated on enzymes encoded by the herpes simplex virus (HSV) and the hepatitis C virus (HCV). Helicase inhibitors that target the HSV helicase-primase complex comprised of the UL5, UL8 and UL52 proteins have recently been shown to effectively control HSV infection in animal models. In addition, several groups have reported structures of the HCV NS3 helicase at atomic resolutions, and mechanistic studies have uncovered characteristics that distinguish the HCV helicase from related cellular proteins. These new developments should eventually lead to new antiviral medications.

Citing Articles

A Comprehensive Survey on the Expediated Anti-COVID-19 Options Enabled by Metal Complexes-Tasks and Trials.

Gopal J, Muthu M, Sivanesan I Molecules. 2023; 28(8).

PMID: 37110587 PMC: 10143858. DOI: 10.3390/molecules28083354.

Flavivirus proteases: The viral Achilles heel to prevent future pandemics.

Teramoto T, Choi K, Padmanabhan R Antiviral Res. 2022; 210:105516.

PMID: 36586467 PMC: 10062209. DOI: 10.1016/j.antiviral.2022.105516.

Punicalagin as an allosteric NSP13 helicase inhibitor potently suppresses SARS-CoV-2 replication in vitro.

Lu L, Peng Y, Yao H, Wang Y, Li J, Yang Y Antiviral Res. 2022; 206:105389.

PMID: 35985407 PMC: 9381947. DOI: 10.1016/j.antiviral.2022.105389.

Targeting SARS-CoV-2 non-structural protein 13 via helicase-inhibitor-repurposing and non-structural protein 16 through pharmacophore-based screening.

Samdani M, Morshed N, Reza R, Asaduzzaman M, Islam A Mol Divers. 2022; 27(3):1067-1085.

PMID: 35690957 PMC: 9188638. DOI: 10.1007/s11030-022-10468-8.

Metal-based complexes against SARS-CoV-2.

Ioannou K, Vlasiou M Biometals. 2022; 35(4):639-652.

PMID: 35332435 PMC: 8946948. DOI: 10.1007/s10534-022-00386-5.

References

Seybert A, van Dinten L, Snijder E, Ziebuhr J . Biochemical characterization of the equine arteritis virus helicase suggests a close functional relationship between arterivirus and coronavirus helicases. J Virol. 2000; 74(20):9586-93. PMC: 112390. DOI: 10.1128/jvi.74.20.9586-9593.2000. View

Matusan A, Pryor M, Davidson A, Wright P . Mutagenesis of the Dengue virus type 2 NS3 protein within and outside helicase motifs: effects on enzyme activity and virus replication. J Virol. 2001; 75(20):9633-43. PMC: 114534. DOI: 10.1128/JVI.75.20.9633-9643.2001. View

Wong I, Lohman T . A double-filter method for nitrocellulose-filter binding: application to protein-nucleic acid interactions. Proc Natl Acad Sci U S A. 1993; 90(12):5428-32. PMC: 46733. DOI: 10.1073/pnas.90.12.5428. View

Kim J, Morgenstern K, Griffith J, Dwyer M, Thomson J, Murcko M . Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding. Structure. 1998; 6(1):89-100. DOI: 10.1016/s0969-2126(98)00010-0. View

Borowski P, Niebuhr A, Mueller O, Bretner M, Felczak K, Kulikowski T . Purification and characterization of West Nile virus nucleoside triphosphatase (NTPase)/helicase: evidence for dissociation of the NTPase and helicase activities of the enzyme. J Virol. 2001; 75(7):3220-9. PMC: 114115. DOI: 10.1128/JVI.75.7.3220-3229.2001. View

Borowski P, Lang M, Niebuhr A, Haag A, Schmitz H, Schulze Zur Wiesch J . Inhibition of the helicase activity of HCV NTPase/helicase by 1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide-5 '-triphosphate (ribavirin-TP). Acta Biochim Pol. 2002; 48(3):739-44. View

Levin M, Patel S . Helicase from hepatitis C virus, energetics of DNA binding. J Biol Chem. 2002; 277(33):29377-85. DOI: 10.1074/jbc.M112315200. View

Morris P, Byrd A, Tackett A, Cameron C, Tanega P, Ott R . Hepatitis C virus NS3 and simian virus 40 T antigen helicases displace streptavidin from 5'-biotinylated oligonucleotides but not from 3'-biotinylated oligonucleotides: evidence for directional bias in translocation on single-stranded DNA. Biochemistry. 2002; 41(7):2372-8. DOI: 10.1021/bi012058b. View

Kleymann G . Novel agents and strategies to treat herpes simplex virus infections. Expert Opin Investig Drugs. 2003; 12(2):165-83. DOI: 10.1517/13543784.12.2.165. View

10.

Warrener P, Collett M . Pestivirus NS3 (p80) protein possesses RNA helicase activity. J Virol. 1995; 69(3):1720-6. PMC: 188775. DOI: 10.1128/JVI.69.3.1720-1726.1995. View

11.

Morris P, Raney K . DNA helicases displace streptavidin from biotin-labeled oligonucleotides. Biochemistry. 1999; 38(16):5164-71. DOI: 10.1021/bi9822269. View

12.

Matson S, Tabor S, Richardson C . The gene 4 protein of bacteriophage T7. Characterization of helicase activity. J Biol Chem. 1983; 258(22):14017-24. View

13.

Subramanya H, BIRD L, Brannigan J, Wigley D . Crystal structure of a DExx box DNA helicase. Nature. 1996; 384(6607):379-83. DOI: 10.1038/384379a0. View

14.

Earnshaw , Moore , Greenwood , Djaballah , Jurewicz , Murray . Time-Resolved Fluorescence Energy Transfer DNA Helicase Assays for High Throughput Screening. J Biomol Screen. 2000; 4(5):239-248. DOI: 10.1177/108705719900400505. View

15.

Yao N, Hesson T, Cable M, Hong Z, Kwong A, Le H . Structure of the hepatitis C virus RNA helicase domain. Nat Struct Biol. 1997; 4(6):463-7. DOI: 10.1038/nsb0697-463. View

16.

Wilson V, West M, Woytek K, Rangasamy D . Papillomavirus E1 proteins: form, function, and features. Virus Genes. 2002; 24(3):275-90. DOI: 10.1023/a:1015336817836. View

17.

Lebowitz J, McMacken R . The Escherichia coli dnaB replication protein is a DNA helicase. J Biol Chem. 1986; 261(10):4738-48. View

18.

Borowski P, Schalinski S, Schmitz H . Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy. Antiviral Res. 2002; 55(3):397-412. DOI: 10.1016/s0166-3542(02)00096-7. View

19.

Caruthers J, Johnson E, McKay D . Crystal structure of yeast initiation factor 4A, a DEAD-box RNA helicase. Proc Natl Acad Sci U S A. 2000; 97(24):13080-5. PMC: 27181. DOI: 10.1073/pnas.97.24.13080. View

20.

Cho H, Ha N, Kang L, Chung K, Back S, Jang S . Crystal structure of RNA helicase from genotype 1b hepatitis C virus. A feasible mechanism of unwinding duplex RNA. J Biol Chem. 1998; 273(24):15045-52. DOI: 10.1074/jbc.273.24.15045. View