ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.

Borowski, Peter; Mueller, Oliver; Niebuhr, Andreas; Kalitzky, Matthias; Hwang, Lih Hwa; Schmitz, Herbert; Siwecka, Maria A.; Kulikowsk, T

doi:10.18388/abp.2000_4075

Cited by 46 publications

(59 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the other hand the nucleoside analogues inhibit the enzyme activity by blocking the ATP-binding site of helicase resulting in uncoupling the ATPase and helicase activities and therefore operate via interaction with the enzyme. These compounds have been used in previous studies to block the helicase activity of hepatitis C virus (Borowski et al, 1999(Borowski et al, , 2000. It has also been suggested that poxviruses, papovaviruses, some RNA viruses such as West Nile virus, severe acute respiratory syndrome coronavirus and dengue virus encoded viral helicases can be probable antiviral drug targets (Kwong et al, 2005).…”

Section: Helicase As Drug Targetmentioning

confidence: 99%

Unraveling the ‘DEAD-box’ helicases of Plasmodium falciparum

Tuteja

Pradhan

2006

Gene

View full text Add to dashboard Cite

The causative agent for the most fatal form of malaria, Plasmodium falciparum, has developed insecticide and drug resistance with time. Therefore combating this disease is becoming increasingly difficult and this calls for finding alternate ways to control malaria. One of the feasible ways could be to find out inhibitors/drugs specific for the indispensable enzymes of malaria parasite such as helicases. These helicases, which contain intrinsic nucleic acid-dependent ATPase activity, are capable of enzymatically unwinding energetically stable duplex nucleic acids into single-stranded templates and are required for all the nucleic acid transactions. Most of the helicases contain a set of nine extremely conserved amino acid sequences, which are called 'helicase motifs'. Due to the presence of the DEAD (Asp-Glu-Ala-Asp) in one of the conserved motifs, this family is also known as the 'DEAD-box' family. In this review, using bioinformatic approach, we describe the 'DEAD-box' helicases of malaria parasite P. falciparum. An in depth analysis shows that the parasite contains 22 full-length genes, some of which are homologues of well-characterized helicases of this family from other organisms. Recently we have cloned and characterized the first member of this family, which is a homologue of p68 and is expressed during the schizont stage of the development of the parasite [Pradhan, A., Chauhan, V.S., Tuteja, R., 2005a. A novel 'DEAD-box' DNA helicase from Plasmodium falciparum is homologous to p68. Mol. Biochem. Parasitol. 140, 55-60.; Pradhan A., Chauhan V.S., Tuteja R., 2005b. Plasmodium falciparum DNA helicase 60 is a schizont stage specific, bipolar and dual helicase stimulated by PKC phosphorylation. Mol. Biochem. Parasitol. 144, 133-141.]. It will be really interesting to clone and characterize other members of the 'DEAD-box' family and understand their role in the replication and transmission of the parasite. These detailed studies may help to identify a parasite-specific enzyme, which could be a potential drug target to treat malaria. The various steps at which this probable drug can act are also discussed.

show abstract

Section: Helicase As Drug Targetmentioning

confidence: 99%

Unraveling the ‘DEAD-box’ helicases of Plasmodium falciparum

Tuteja

Pradhan

2006

Gene

View full text Add to dashboard Cite

show abstract

“…This derivative is able to block the NTPbinding site (IC 50 = 22 μM) and to inhibit the ATPase activity (IC 50 = 17 μM) in a competitive way, but is not able to inhibit the helicase activity at concentration lower than 1 mM [14] The partial unwinding activity mediated by these competitive NTPase inhibitors is common to all members of the class, and the concentrations needed for the helicase inhibition usually exceed the IC 50 value by 3-5 times. At these concentrations, the NTPase activity reached 10-35% of the control [46][47][48]. The basis for the phenomenon remains unclear.…”

Section: Inhibition Of Ntpase Activity By Interference With Ntpmentioning

confidence: 93%

“…Consequently, non-(or slowly) hydrolysable ATP-analogs seemed to be effective tools for inhibiting the helicase activity, like adenosine-5 γ-thiotriphosphate (ATP-γ-S), which is used to determine a low level of unwinding of HCV dsRNA [44,45]. However, ribavirin 5 -triphosphate (RTP), that inhibits the HCV NTPase/helicase by a competitive mechanism in regard to ATP [46], and ribavirin 5 -diphosphate (RDP), both reported in Figure 3, even showing IC 50 values in the micromolar range, demonstrates to determine only a weakly enzymatic inhibition [34]. The same behavior has been put in evidence for paclitaxel, compound structurally nonrelated to NTP.…”

Section: Inhibition Of Ntpase Activity By Interference With Ntpmentioning

confidence: 99%

“…An example is the calmodulin antagonist trifluoperazine (62, Figure 13). Although the molecule is known to interact with domain 1 of HCV helicase, it is uncertain if inhibition results from conformational changes or from blockage of the ATPbinding site [46]. Even some tropolones have been screened as inhibitors of HCV helicase-catalyzed DNA unwinding.…”

Section: Inhibition Of Ntpase Activity By Allosteric Mechanismsmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of RNA Helicases of ssRNA⁺ Virus Belonging to Flaviviridae, Coronaviridae and Picornaviridae Families

Briguglio

Piras

Corona

et al. 2011

International Journal of Medicinal Chemistry

View full text Add to dashboard Cite

Many viral pathogens encode the motor proteins named RNA helicases which display various functions in genome replication. General strategies to design specific and selective drugs targeting helicase for the treatment of viral infections could act via one or more of the following mechanisms: inhibition of the NTPase activity, by interferences with ATP binding and therefore by limiting the energy required for the unwinding and translocation, or by allosteric mechanism and therefore by stabilizing the conformation of the enzyme in low helicase activity state; inhibition of nucleic acids binding to the helicase; inhibition of coupling of ATP hydrolysis to unwinding; inhibition of unwinding by sterically blocking helicase translocation. Recently, by in vitro screening studies, it has been reported that several benzotriazole, imidazole, imidazodiazepine, phenothiazine, quinoline, anthracycline, triphenylmethane, tropolone, pyrrole, acridone, small peptide, and Bananin derivatives are endowed with helicase inhibition of pathogen viruses belonging to Flaviviridae, Coronaviridae, and Picornaviridae families.

show abstract

“…As shown in FIG. 5b, assays can be used to identify small-molecule helicase inhibitors that have the following effects: they inhibit NTPase activity by direct competition with NTP binding 69 ; competitively inhibit nucleic-acid binding; inhibit NTP hydrolysis or NDP release by blocking the movement of domain 2; inhibit the process that couples NTP hydrolysis to translocation and unwinding of nucleic acid; inhibit unwinding by sterically blocking helicase translocation 70 ; and inhibit unwinding (reviewed in REFS 14,71). For all these mechanisms, unwinding and binding assays can be deployed.…”

Section: Strategies For Discovering Inhibitorsmentioning

confidence: 99%

Viral and cellular RNA helicases as antiviral targets

Kwong

Rao

Jeang

2005

Nat Rev Drug Discov

200

188

View full text Add to dashboard Cite

Although there has been considerable progress in the development of antiviral agents in recent years, there is still a pressing need for new drugs both to improve on the properties of existing agents and to combat the problem of viral resistance. Helicases, both viral and human, have recently emerged as novel targets for the treatment of viral infections. Here, we discuss the role of these enzymes, factors affecting their potential as drug targets and progress in the development of agents that inhibit their activity using the hepatitis C virus-encoded helicase NS3 and the cellular helicase DDX3 adopted for use by HIV-1 as examples.

show abstract

ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.

Cited by 46 publications

References 33 publications

Unraveling the ‘DEAD-box’ helicases of Plasmodium falciparum

Unraveling the ‘DEAD-box’ helicases of Plasmodium falciparum

Inhibition of RNA Helicases of ssRNA⁺ Virus Belonging to Flaviviridae, Coronaviridae and Picornaviridae Families

Viral and cellular RNA helicases as antiviral targets

Contact Info

Product

Resources

About

ATP-binding domain of NTPase/helicase as a target for hepatitis C antiviral therapy.

Cited by 46 publications

References 33 publications

Unraveling the ‘DEAD-box’ helicases of Plasmodium falciparum

Unraveling the ‘DEAD-box’ helicases of Plasmodium falciparum

Inhibition of RNA Helicases of ssRNA+ Virus Belonging to Flaviviridae, Coronaviridae and Picornaviridae Families

Viral and cellular RNA helicases as antiviral targets

Contact Info

Product

Resources

About

Inhibition of RNA Helicases of ssRNA⁺ Virus Belonging to Flaviviridae, Coronaviridae and Picornaviridae Families