New Peptide Inhibitors of Type IB Topoisomerases: Similarities and Differences Vis-a-vis Inhibitors of Tyrosine Recombinases

Fujimoto, David F.; Pinilla, Clemencia; Segall, Anca M.

doi:10.1016/j.jmb.2006.08.052

Cited by 15 publications

(19 citation statements)

References 44 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). The antineoplastic agent, mitoxantrone, was also reported to inhibit the replication process at the stage of virion assembly and mutations mapped to the DNA ligase (Deng et al, 2007).…”

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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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%

Orthopoxvirus targets for the development of new antiviral agents

Prichard

Kern

2012

Antiviral Research

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“…The activity of many of these peptides, such as WRWYCR (Supplemental information Figure 1B), is not dependent upon interactions with any of the proteins required for recombination. In fact, these peptides inhibit several mechanistically distinct tyrosine recombinases3, 4, DNA cleavage and HJ resolution by Vaccinia virus topoisomerase5, 6, and structurally unrelated HJ processing enzymes like RecG helicase and RuvABC resolvase7. All of these activities are based on the ability of the peptides to bind to protein-free HJs, and with somewhat lesser affinity to other branched DNAs and replication forks7.…”

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Small molecule functional analogs of peptides that inhibit λ site-specific recombination and bind Holliday junctions

Ranjit

Rideout

Nefzi

et al. 2010

Bioorganic & Medicinal Chemistry Letters

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Our lab has isolated hexameric peptides that are structure-selective ligands of Holliday junctions (HJ), central intermediates of several DNA recombination reactions. One of the most potent of these inhibitors, WRWYCR, has shown antibacterial activity in part due to its inhibition of DNA repair proteins. To increase the therapeutic potential of these inhibitors, we searched for small molecule inhibitors with similar activities. We screened 11 small molecule libraries comprising over nine million individual compounds and identified a potent N-methyl aminocyclic thiourea inhibitor that also traps HJs formed during site-specific recombination reactions in vitro. This inhibitor binds specifically to protein free HJs and can inhibit HJ resolution by RecG helicase, but only showed modest growth inhibition of bacterial with a hyperpermeable outer membrane; nonetheless, this is an important step in developing a functional analog of the peptide inhibitors.

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“…We have previously identified and characterized hexapeptides that inhibit site-specific recombination by the phage lambda Int in vitro by binding to the Holliday junction (HJ) intermediates of the reaction and preventing their resolution (4,7,13,22). The most potent of these peptides (WRWYCR, KWWCRW, and related peptides) were subsequently found to be bactericidal, very likely due to their causing the accumulation of DNA breaks and inhibiting chromosome segregation (18; C. Gunderson and A. Segall, unpublished data).…”

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Peptide wrwycr Inhibits the Excision of Several Prophages and Traps Holliday Junctions inside Bacteria

et al. 2009

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Peptide inhibitors of phage lambda site-specific recombination were previously isolated by screening synthetic combinatorial peptide libraries. These inhibitors cause the accumulation of complexes between the recombinase and the Holliday junction intermediate of several highly divergent tyrosine recombinases. Peptide WRWYCR and its D-amino acid derivative bind to the center of protein-free junctions and prevent their resolution either by site-specific recombinases or by junction resolvases or helicases. With lesser affinity, the peptides also bind to branched DNA molecules that mimic replication forks. The peptides are bactericidal to both gram-positive and gram-negative bacteria, presumably because they can interfere with DNA repair and with chromosome dimer resolution by the XerC and XerD tyrosine recombinases. In order to test the correspondence between their mechanism in vivo and in vitro, we have tested and shown peptide wrwycr's ability to inhibit the excision of several prophages (lambda, P22, Gifsy-1, Gifsy-2, Fels-1, Fels-2) and to trap Holliday junction intermediates of phage lambda site-specific recombination in vivo. In addition, we found that the peptide inhibits replication of the Salmonella prophage Fels-1 while integrated in the chromosome. These findings further support the proposed mechanistic basis for the antimicrobial activity of the peptide and its use as a tool to dissect strand exchange-dependent DNA repair within cells.Bacteriophage lambda uses a phage-encoded integrase (Int) to catalyze the site-specific recombination reaction that integrates its chromosome into and excises it out of the Escherichia coli chromosome (e.g., see references 2 and 34). We have previously identified and characterized hexapeptides that inhibit site-specific recombination by the phage lambda Int in vitro by binding to the Holliday junction (HJ) intermediates of the reaction and preventing their resolution (4,7,13,22). The most potent of these peptides (WRWYCR, KWWCRW, and related peptides) were subsequently found to be bactericidal, very likely due to their causing the accumulation of DNA breaks and inhibiting chromosome segregation (18; C. Gunderson and A. Segall, unpublished data). In vivo, however, the D-amino acid forms of the peptides (wrwycr and kwwcrw) were more potent than their L-form counterparts, presumably because they resist peptidases (18).The question remains whether these peptides block sitespecific recombination and accumulate HJ inside bacterial cells. Int is the archetype of a large family of site-specific recombinases that use a tyrosine nucleophile for sequential transesterification reactions. The LT2 strain of Salmonella enterica serovar Typhimurium has four naturally occurring prophages (bacteriophages integrated in its chromosome): Gifsy-1, Gifsy-2, Fels-1, and Fels-2 (11, 15, 36). Each of these prophages encodes an Int-like tyrosine recombinase and can be induced to excise and replicate in a manner very similar to that of phage lambda. DNA damage is the predominant signal that leads to ...

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New Peptide Inhibitors of Type IB Topoisomerases: Similarities and Differences Vis-a-vis Inhibitors of Tyrosine Recombinases

Cited by 15 publications

References 44 publications

Orthopoxvirus targets for the development of new antiviral agents

Orthopoxvirus targets for the development of new antiviral agents

Small molecule functional analogs of peptides that inhibit λ site-specific recombination and bind Holliday junctions

Peptide wrwycr Inhibits the Excision of Several Prophages and Traps Holliday Junctions inside Bacteria

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