Peptidomimetic Inhibitors of Herpes Simplex Virus Ribonucleotide Reductase with Improved <i>in Vivo</i> Antiviral Activity

Moss, Neil; Beaulieu, Pierre L.; Duceppe, Jean‐Simon; Ferland, Jean-Marie; Garneau, Michel; Gauthier, Jean; Ghiro, Élise; Goulet, Sylvie; Guse, Ingrid; Jaramillo, Jorge; Llinàs‐Brunet, Montse; Malenfant, Éric; Plante, Raymond; Poirier, Martin; Soucy, François; Wernic, Dominik; Yoakim, Christiane; Déziel, Robert

doi:10.1021/jm960324r

Cited by 40 publications

(22 citation statements)

References 20 publications

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“…In vivo studies with some of the inhibitors developed by Moss et al [78] were even more enthusiastic since it was observed that the inhibitors were able to effectively reduce the severity of the virus in most of the cases, without interfering with the infected host. The latest developments of antisense technology allow to conclude that the inhibition of RNR can be performed in a pre-translation phase, which has several advantages over the other types of inhibition: i) they become very specific for the corresponding mRNA of that protein, and therefore of each organism and ii) taking this specificity in account it may decrease the toxicity or even the number of secondary effects that normally follows the other kind of inhibitors [65].…”

Section: Rnr Peptide Inhibition Began With the Discovery Bymentioning

confidence: 99%

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Cerqueira¹,

Pereira²,

Fernandes³

et al. 2005

CMC

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This review provides up-to-date information on the inhibition of ribonucleotide reductase (RNR), the enzyme that catalyses the reduction of ribonucleotides into deoxyribonucleotides. Taking in account that DNA replication and repair are essential mechanisms for cell integrity and are dependent on the availability of deoxyribonucleotides, many researchers are giving special attention to this enzyme, since it is an attractive target to treat several diseases of our time specially cancer. This investment has already given some benefits since some of these inhibitors show potent chemotherapeutic efficacy against a wide range of tumours such as non-small cell lung cancer, adenocarcinoma of pancreas, bladder cancer, leukaemia and some solid tumours. In fact a few of them have already been approved for the clinical treatment of some kinds of cancer. All aspects of RNR inhibition and corresponding inhibitors are the subjects of this review. The inhibitors are divided in three main groups: translation inhibitors, which unable the formation of the enzyme; dimerization inhibitors that prevent the complexation of the two RNR subunits (R1 and R2); and catalytic inhibitors that inactivate subunit R1 and/or subunit R2, leading to RNR inactivity. In this last group special focus will be addressed to substrate analogues.

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Section: Rnr Peptide Inhibition Began With the Discovery Bymentioning

confidence: 99%

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Cerqueira¹,

Pereira²,

Fernandes³

et al. 2005

CMC

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“…Hence, C-terminal Rnr2-based peptidomimetics (14-16) bind Rnr1, blocking RNR assembly and providing another mode of therapy for proliferative diseases such as cancer. Early reports on Rnr2 peptide-based inhibitors showed that they had in vivo efficacy against herpes simplex virus with nM dissociation constants (17)(18)(19), suggesting that similar potencies might be possible with anticancer peptidomimetics.…”

mentioning

confidence: 99%

Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly

Faber

Uchiki

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Ribonucleotide reductase (RNR) catalyzes the conversion of nucleoside diphosphates to deoxynucleoside diphosphates. Crucial for rapidly dividing cells, RNR is a target for cancer therapy. In eukaryotes, RNR comprises a heterooligomer of ␣2 and ␤2 subunits. Rnr1, the ␣ subunit, contains regulatory and catalytic sites; Rnr2, the ␤ subunit (in yeast, a heterodimer of Rnr2 and Rnr4), houses the diferric-tyrosyl radical crucial for catalysis. Here, we present three x-ray structures of eukaryotic Rnr1 from Saccharomyces cerevisiae: one bound to gemcitabine diphosphate (GemdP), the active metabolite of the mechanism-based chemotherapeutic agent gemcitabine; one with an Rnr2-derived peptide, and one with an Rnr4-derived peptide. Our structures reveal that GemdP binds differently from its analogue, cytidine diphosphate; because of unusual interactions of the geminal fluorines, the ribose and base of GemdP shift substantially, and loop 2, which mediates substrate specificity, adopts different conformations when binding to GemdP and cytidine diphosphate. The Rnr2 and Rnr4 peptides, which block RNR assembly, bind differently from each other but have unique modes of binding not seen in prokaryotic RNR. The Rnr2 peptide adopts a conformation similar to that previously reported from an NMR study for a mouse Rnr2-based peptide. In yeast, the Rnr2 peptide binds at subsites consisting of residues that are highly conserved among yeast, mouse, and human Rnr1s, suggesting that the mode of Rnr1-Rnr2 binding is conserved among eukaryotes. These structures provide new insights into subunit assembly and a framework for structure-based drug design targeting RNR.allosteric regulation ͉ crystallography ͉ dNTP ͉ chemotherapy ͉ gemcitabine R ibonucleotide reductases (RNRs) catalyze the reduction of ribonucleotides to deoxyribonucleotides, essential precursors of DNA synthesis. Crucial for rapidly proliferating cells, RNR is a target for anticancer (1, 2) and antiviral (2, 3) drugs. Gemcitabine, an analogue of deoxycytidine (2Ј-2Ј-difluorodeoxycytidine), is sequentially phosphorylated to the 5Ј-monophosphate form by deoxycytidine kinase and to difluorodeoxycytidine 5Ј-diphosphate (GemdP) by uridylate-cytidylate monophosphate kinase. In the presence of reductants, GemdP inactivates Rnr1. In the absence of reductants, with prereduced Rnr1 and Rnr2, inhibition occurs from the loss of the tyrosyl radical in Rnr2 (1). Recently, GemdP has been shown to inactivate both human R1 and R2 (JoAnne Stubbe, personal communication). Inhibition of RNR by GemdP leads to reduction of the pool of deoxyribonucleotide 5Ј-diphosphates available for DNA synthesis, presumably favoring incorporation of the gemcitabine triphosphate metabolite by DNA polymerase ␣, preventing chain elongation (4, 5).RNRs require unusual metallocofactors to initiate radicalbased nucleotide reduction and are divided into three classes based on their cofactor. Class I RNR, found in all eukaryotes, is a heterooligomer of ␣ 2 and ␤ 2 subunits (6). In eukaryotes, the ␣ subunit, called Rnr1, c...

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“…20 In this latter work, reviewed in Ref. 21, assays of HSV-RR inhibition were performed under conditions that would be expected to favor R1 2 formation.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of action of peptide inhibitors of mammalian ribonucleotide reductase targeting quaternary structure

et al. 2004

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Mammalian ribonucleotide reductase (mRR) is a chemotherapeutic target. The enzyme is composed of 2 subunits (mR1 and mR2) and is inhibited by Ac-FTLDADF (denoted P7), corresponding to the C-terminus of mR2, which competes with mR2 for binding to mR1. mRR has 2 physiologically important active forms, mR12mR22 and mR16(mR22)j (j = 1-3). Here we report on the mechanism of action of recently identified peptide derivatives having higher activities than P7 toward inhibition of one or both active forms. A significant feature of both P7 and these new inhibitors is that they are more potent vs. mR12mR22 than mR16(mR22)j. For some of these peptides, this is due in part to their preferential binding to the mR1 monomer. The possible application of these peptide derivatives in cancer chemotherapy is discussed.

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Peptidomimetic Inhibitors of Herpes Simplex Virus Ribonucleotide Reductase with Improved in Vivo Antiviral Activity

Cited by 40 publications

References 20 publications

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Overview of Ribonucleotide Reductase Inhibitors: An Appealing Target in Anti-Tumour Therapy

Structures of eukaryotic ribonucleotide reductase I define gemcitabine diphosphate binding and subunit assembly

Mechanisms of action of peptide inhibitors of mammalian ribonucleotide reductase targeting quaternary structure

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