A potent peptidomimetic inhibitor of HSV ribonucleotide reductase with antiviral activity in vivo

Liuzzi, Michel; Déziel, Robert; N, Moss; Beaulieu, Pierre L.; Bonneau, A M; Bousquet, Christiane; Chafouleas, James G.; Garneau, Michel; Jaramillo, Jorge; Krogsrud, Richard L.; Lagacé, Lisette; McCollum, Robert S.; Nawoot, S; Guindon, Yvan

doi:10.1038/372695a0

Cited by 133 publications

(88 citation statements)

References 29 publications

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“…Some proteins act as oligomer complexes, so IDs may prevent formation of the active dimer. Such inhibitors have been discovered for three HIV enzymes (protease, reverse transcriptase, invertase) [117,[139][140][141], ribonucleotide reductase [142], DNA polymerase of herpes simplex virus [143], human gluthatione reductase [144], phosphatidylinisitol 3-kinase [145] etc.…”

Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

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Section: Inhibitors Of Dimerizationmentioning

confidence: 99%

Protein‐protein interactions as a target for drugs in proteomics

et al. 2003

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“…The enzyme can be inhibited by nucleotide analogs, by reduction of the essential tyrosyl radical and by preventing subunit interaction [7,20,21]. In addition, interferring with the supply of reducing equivalents should strongly influence the activity of ribonucleotide reductase.…”

Section: Discussionmentioning

confidence: 99%

“…Ribonucleotide reductase is an attractive target molecule for anticancer and antimicrobial drug development [21,22]. The enzyme can be inhibited by nucleotide analogs, by reduction of the essential tyrosyl radical and by preventing subunit interaction [7,20,21].…”

Section: Discussionmentioning

confidence: 99%

“…Interaction between the R1 and R2 proteins is entirely accounted for by the carboxy terminus of the small subunit [15,20]. Synthetic peptides containing the seven C-terminal residues of R2 are selective inhibitors of mammalian [20], viral [21] and probably plasmodial [22] ribonucleotide reductases.…”

Section: Sequence Comparison Of 72 Brucei R2 With Other R2 Proteinsmentioning

confidence: 99%

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Cloning, sequencing and expression of ribonucleotide reductase R2 from Trypanosoma brucei

et al. 1997

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As a first step towards the understanding of the trypanosomal synthesis of deoxyribonucleotides we describe the cloning of the gene of ribonucleotide reductase subunit R2 from 72 brucei hrucei and its overexpression in E. coli. Materials and methods DNA and RNA preparation2;4 l08 long slender 72 brucei cells were suspended in 10 mM Tris-HC1, 250 mM NaCI, 0.5% Nonidet P-40, pH 8.0. After 5 rain incubation on ice the suspension was centrifuged and the cell pellet was homogenized in 200 lal 10 mM Tris-HC1, 10 mM NaC1, 10 mM EDTA, 0.5% SDS, pH 8.0. 50 lag proteinase K were added and the mixture was incubated for 1 h at 37°C. DNA was purified by phenol extraction.RNA was isolated from bloodstream long slender and short stumpy as well as procyclic stages of 72 brucei using the RNA Easy Kit (Qiagen) according to the instructions of the manufacturer.

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“…The specificity of peptide inhibitors was first demonstrated for a nonapeptide that inhibited the herpes simplex virus (HSV) RNR without affecting the activity of the mammalian enzyme (32,33). This observation led to the develop-ment of potent peptidomimetic inhibitors of HSV RNR with antiviral activity in vivo (34). The inhibitory effect of R2 C-terminal peptides has also been demonstrated for mammalian (35,36) and E. coli class Ia (37) RNRs.…”

mentioning

confidence: 99%

Cloning and characterization of the R1 and R2 subunits of ribonucleotide reductase from Trypanosoma brucei

Hofer

Schmidt

Gräslund

et al. 1997

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

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Ribonucleotide reductase (RNR) catalyzes the rate limiting step in the de novo synthesis of deoxyribonucleotides by directly reducing ribonucleotides to the corresponding deoxyribonucleotides. To keep balanced pools of deoxyribonucleotides, all nonviral RNRs studied so far are allosterically regulated. Most eukaryotes contain a class I RNR, which is a heterodimer of two nonidentical subunits called proteins R1 and R2. We have isolated cDNAs encoding the R1 and R2 proteins from Trypanosoma brucei. The amino acid sequence identities with the mouse R1 and R2 subunits are 58% and 63%, respectively. Recombinant active trypanosome R1 and R2 proteins were expressed in Escherichia coli and purified. The R2 protein contains an iron-tyrosyl free radical center verified by EPR spectroscopy and iron analyses. Measurement of cytidine 5 -diphosphate reduction by the trypanosome RNR in the presence of various allosteric effectors showed that the activity is highest with dTTP, dGTP, or dATP and considerably lower with ATP. The effect of dGTP is either activating (alone) or inhibitory (in the presence of ATP). Filter binding studies indicated that there are two classes of allosteric effector binding sites that bind ATP or dATP (low-affinity dATP site) and ATP, dATP, dGTP, or dTTP (high-affinity dATP site), respectively. Therefore, the structural organization of the allosteric sites is very similar to the mammalian RNRs, whereas the allosteric regulation of cytidine 5 -diphosphate reduction is unique. Hopefully, this difference can be used to target the trypanosome RNR for therapeutic purposes.Sleeping sickness is a major health problem in a predominant part of sub-Saharan Africa. The disease, caused by a unicellular eukaryote called Trypanosoma brucei (1), is usually fatal if left untreated, and Ϸ25,000 new cases are diagnosed each year. However, since only a small fraction of the population in high risk areas is under surveillance, the World Health Organization has estimated the real figure to be Ϸ300,000. ‡ The current chemotherapy of sleeping sickness suffers from various limitations. Many of the compounds used are highly toxic and there is also a widespread drug resistance among the trypanosomes (2, 3).Ribonucleotide reductase (RNR) catalyzes the reduction of ribonucleotides to deoxyribonucleotides. There are three different classes of RNRs (4). The substrate, which is a nucleoside diphosphate for the class I enzymes, is reduced through a radical mechanism. Class I RNR is a heterodimeric enzyme of ␣ 2 ␤ 2 type. The large R1 subunit binds substrates and allosteric effectors, while the small R2 subunit contains a tyrosyl radical (5), generated by a binuclear ferric iron center. The tyrosyl radical in the R2 protein is linked to the active site in the R1 subunit through a hydrogen-bonded long-range electron transport chain (6-10). Class II RNR generates a radical from 5Ј-deoxyadenosylcobalamin (11, 12) and class III RNR, which only works under anaerobic conditions, contains a stable glycyl radical (13). Class I and to s...

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A potent peptidomimetic inhibitor of HSV ribonucleotide reductase with antiviral activity in vivo

Cited by 133 publications

References 29 publications

Protein‐protein interactions as a target for drugs in proteomics

Protein‐protein interactions as a target for drugs in proteomics

Cloning, sequencing and expression of ribonucleotide reductase R2 from Trypanosoma brucei

Cloning and characterization of the R1 and R2 subunits of ribonucleotide reductase from Trypanosoma brucei

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