Fluoroquinolone-dependent DNA Supercoiling by Vaccinia Topoisomerase I

Kamau, Edwin; Grove, Anne

doi:10.1016/j.jmb.2004.06.082

Cited by 10 publications

(10 citation statements)

References 43 publications

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“…Although the virus topoisomerase is not strictly required for vaccinia virus replication its function appears to be important since some quinolone analogs have been reported to inhibit its enzymatic activity (Kamau and Grove, 2004), and related analogs have been shown to inhibit viral replication (Sekiguchi and Shuman, 1997b). Additional specific inhibitors of the viral topoisomerase enzymatic activity have been identified but their antiviral activity has not been reported (Bond et al, 2006; Fujimoto et al, 2006; Yakovleva et al, 2004).…”

Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 99%

“…The viral proteases are obvious targets for the development of specific inhibitors of vaccinia virus and experience with HIV illustrates the tremendous potential of protease inhibitors. Specific inhibitors of I7L activity, such as TTP-6171, have been described and continued efforts will likely yield a number of candidate compounds that have potential for the treatment of orthopoxvirus infections (Byrd et al, 2004; Katritch et al, 2007). …”

Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 99%

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Orthopoxvirus targets for the development of new antiviral agents

Prichard

Kern

2012

Antiviral Research

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Investments in the development of new drugs for orthopoxvirus infections have fostered new avenues of research, provided an improved understanding of orthopoxvirus biology and yielded new therapies that are currently progressing through clinical trials. These broad-based efforts have also resulted in the identification of new inhibitors of orthopoxvirus replication that target many different stages of viral replication cycle. This review will discuss progress in the development of new anti-poxvirus drugs and the identification of new molecular targets that can be exploited for the development of new inhibitors. The prototype of the orthopoxvirus group is vaccinia virus and its replication cycle will be discussed in detail noting specific viral functions and their associated gene products that have the potential to serve as new targets for drug development. Progress that has been achieved in recent years should yield new drugs for the treatment of these infections and might also reveal new approaches for antiviral drug development with other viruses.

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Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 99%

Section: Potential Molecular Targets In Orthopoxvirus Replication mentioning

confidence: 99%

Orthopoxvirus targets for the development of new antiviral agents

Prichard

Kern

2012

Antiviral Research

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“…Furthermore, it was demonstrated that ofloxacin [68] and levofloxacin [69] inhibited viral topoisomerase activity of vaccinia virus but not of herpes simplex virus and influenza virus [68]. In agreement with this finding, it was reported that 200 mg/L each of ciprofloxacin, lomefloxacin, ofloxacin, pefloxacin, and rufloxacin inhibited to 50 % the cytopathic effect of herpes simplex virus type 2 at concentrations being equivalent to the cytotoxic effect of the quinolones on the Vero cells [70].…”

Section: Antiviral Activities Of Fluoroquinolonesmentioning

confidence: 53%

Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action?

Dalhoff¹

2014

Eur J Clin Microbiol Infect Dis

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This review summarizes evidence that commercially available fluoroquinolones used for the treatment of bacterial infections are active against other non-bacterial infectious agents as well. Any of these fluoroquinolones exerts, in parallel to its antibacterial action, antiviral, antifungal, and antiparasitic actions at clinically achievable concentrations. This broad range of anti-infective activities is due to one common mode of action, i.e., the inhibition of type II topoisomerases or inhibition of viral helicases, thus maintaining the selective toxicity of fluoroquinolones inhibiting microbial topoisomerases at low concentrations but mammalian topoisomerases at much higher concentrations. Evidence suggests that standard doses of the fluoroquinolones studied are clinically effective against viral and parasitic infections, whereas higher doses administered topically were active against Candida spp. causing ophthalmological infections. Well-designed clinical studies should be performed to substantiate these findings.

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“…It was demonstrated that ofloxacin and levofloxacin inhibited the viral topoisomerase activity of the vaccinia virus but not of the herpes simplex virus and influenza virus [ 15 ]. A previous report also showed that fluoroquinolone enrofloxacin inhibits DNA relaxation by Vaccinia topoisomerase I [ 16 ]. Therefore, we chose ofloxacin as a positive inhibitor compared with other natural compounds, looking at the amount of 4103 compounds that were successfully sifted against TOP1.…”

Section: Resultsmentioning

confidence: 99%

Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I

Chu

et al. 2023

Molecules

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The monkeypox outbreak has become a global public health emergency. The lack of valid and safe medicine is a crucial obstacle hindering the extermination of orthopoxvirus infections. The identification of potential inhibitors from natural products, including Traditional Chinese Medicine (TCM), by molecular modeling could expand the arsenal of antiviral chemotherapeutic agents. Monkeypox DNA topoisomerase I (TOP1) is a highly conserved viral DNA repair enzyme with a small size and low homology to human proteins. The protein model of viral DNA TOP1 was obtained by homology modeling. The reliability of the TOP1 model was validated by analyzing its Ramachandran plot and by determining the compatibility of the 3D model with its sequence using the Verify 3D and PROCHECK services. In order to identify potential inhibitors of TOP1, an integrated library of 4103 natural products was screened via Glide docking. Surface Plasmon Resonance (SPR) was further implemented to assay the complex binding affinity. Molecular dynamics simulations (100 ns) were combined with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations to reveal the binding mechanisms of the complex. As a result, three natural compounds were highlighted as potential inhibitors via docking-based virtual screening. Rosmarinic acid, myricitrin, quercitrin, and ofloxacin can bind TOP1 with KD values of 2.16 μM, 3.54 μM, 4.77 μM, and 5.46 μM, respectively, indicating a good inhibitory effect against MPXV. The MM/PBSA calculations revealed that rosmarinic acid had the lowest binding free energy at −16.18 kcal/mol. Myricitrin had a binding free energy of −13.87 kcal/mol, quercitrin had a binding free energy of −9.40 kcal/mol, and ofloxacin had a binding free energy of −9.64 kcal/mol. The outputs (RMSD/RMSF/Rg/SASA) also indicated that the systems were well-behaved towards the complex. The selected compounds formed several key hydrogen bonds with TOP1 residues (TYR274, LYS167, GLY132, LYS133, etc.) via the binding mode analysis. TYR274 was predicted to be a pivotal residue for compound interactions in the binding pocket of TOP1. The results of the enrichment analyses illustrated the potential pharmacological networks of rosmarinic acid. The molecular modeling approach may be acceptable for the identification and design of novel poxvirus inhibitors; however, further studies are warranted to evaluate their therapeutic potential.

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Fluoroquinolone-dependent DNA Supercoiling by Vaccinia Topoisomerase I

Cited by 10 publications

References 43 publications

Orthopoxvirus targets for the development of new antiviral agents

Orthopoxvirus targets for the development of new antiviral agents

Antiviral, antifungal, and antiparasitic activities of fluoroquinolones optimized for treatment of bacterial infections: a puzzling paradox or a logical consequence of their mode of action?

Potential Inhibitors of Monkeypox Virus Revealed by Molecular Modeling Approach to Viral DNA Topoisomerase I

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