Specific inhibition of herpesvirus ribonucleotide reductase by synthetic peptides

Dutia, Bernadette M.; Frame, Margaret C.; Subak‐Sharpe, J. H.; Clark, William N.; Marsden, Howard S.

doi:10.1038/321439a0

Cited by 211 publications

(139 citation statements)

References 15 publications

Supporting

Mentioning

133

Contrasting

Order By: Relevance

“…Because protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and viral replication, inhibition of these interactions is a promising novel approach for rational drug design against a wide number of cellular and viral targets (17,18). Synthetic peptides that disrupt protein-protein interactions have been successfully shown to act as inhibitors of HIV-1 protease (19), HIV-1 reverse transcriptase (20), herpes simplex virus ribonucleotide reductase (21), and thymidilate synthase (22). Binding of polypeptide hormones, growth factors, or cytokines to cell surface receptors activates dimerization (oligomerization) of the receptors, which leads to the signal transduction to the interior of the cell (23).…”

mentioning

confidence: 99%

Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

Berezov

Chen

Liu

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Members of the erbB family receptor tyrosine kinases (erbB1, erbB2, erbB3, and erbB4) are overexpressed in a variety of human cancers and represent important targets for the structure-based drug design. Homo-and heterodimerization (oligomerization) of the erbB receptors are known to be critical events for receptor signaling. To block receptor self-associations, we have designed a series of peptides derived from potential dimerization surfaces in the extracellular subdomain IV of the erbB receptors (erbB peptides). In surface plasmon resonance (BIAcore) studies, the designed peptides have been shown to selectively bind to the erbB receptor ectodomains and isolated subdomain IV of erbB2 with submicromolar affinities and to inhibit heregulin-in- erbB2 (neu, HER2) is a member of the epidermal growth factor or HER family of tyrosine kinase receptors that also includes erbB1 (EGFR, 1 HER1), erbB3 (HER3), and erbB4 (HER4) (1-4). Overexpression of erbB receptors has been found in many types of human cancer raising the possibility that receptor-directed therapies may be useful as cancer management strategies. Greater expression of erbB2 on transformed cells than on normal epithelial tissues allows selective targeting of tumor cells using various approaches (5-13). A variety of strategies have also been developed for targeting the erbB1 receptor, including monoclonal antibodies, ligand-linked immunotoxins, tyrosine kinase inhibitors, and antisense approaches.Recently, we have reported the design of an anti-erbB2 peptide mimetic, AHNP, derived from the structure of the CDR-H3 loop of the anti-erbB2 monoclonal antibody 4D5 and demonstrated its in vitro and in vivo activities in disabling erbB2 tyrosine kinases similar to the monoclonal antibody (14 -16). We have argued that another interesting approach for disabling erbB receptor activity would be targeting protein-protein interaction surfaces. Because protein-protein interactions play a key role in various mechanisms of cellular growth and differentiation, and viral replication, inhibition of these interactions is a promising novel approach for rational drug design against a wide number of cellular and viral targets (17,18). Synthetic peptides that disrupt protein-protein interactions have been successfully shown to act as inhibitors of HIV-1 protease (19), HIV-1 reverse transcriptase (20), herpes simplex virus ribonucleotide reductase (21), and thymidilate synthase (22). Binding of polypeptide hormones, growth factors, or cytokines to cell surface receptors activates dimerization (oligomerization) of the receptors, which leads to the signal transduction to the interior of the cell (23). Although most of the receptor inhibitors developed to date have been focused on the blockade of receptor-ligand or enzyme-substrate interactions, repression of receptor-receptor interactions that accompany oligomerization might also represent an important target for disabling receptor functioning. This approach has been recently used for the design of peptidic estrogen receptor inhibitors ...

show abstract

mentioning

confidence: 99%

Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

Berezov

Chen

Liu

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Inhibition of this dimerization step would prevent the activation of the viral PR and, in turn, prevent the polyprotein processing, which is essential for viral maturation and infectivity (Kohl et al, 1988). The ability of oligopeptides to interfere with formation of a protein complex has been previously documented in vitro for two herpes simplex virus systems, the enzyme ribonucleotide reductase (Dutia et al, 1986;McClements et al, 1988), and the regulatory protein VP16 (Haigh et al, 1990). Our previous use of defective monomers or nonidentical subunits to exchange with wild-type PR homodimers 1245 in vitro produced catalytically defective heterodimers (Babe et al, 1991).…”

mentioning

confidence: 99%

Synthetic “interface” peptides alter dimeric assembly of the HIV 1 and 2 proteases

1992

View full text Add to dashboard Cite

Retroviral proteases are obligate homodimers and play an essential role in the viral life cycle. Dissociation of dimers or prevention of their assembly may inactivate these enzymes and prevent viral maturation. A salient structural feature of these enzymes is an extended interface composed of interdigitating N-and C-terminal residues of both monomers, which form a four-stranded 6-sheet. Peptides mimicking one 6-strand (residues 95-99), or two &strands (residues 1-5 plus 95-99 or 95-99 plus 95-99) from the human immunodeficiency virus 1 (HIVl) interface were shown to inhibit the HIVl and 2 proteases (PRs) with ICso's in the low micromolar range. These interface peptides show cognate enzyme preference and do not inhibit pepsin, renin, or the Rous sarcoma virus PR, indicating a degree of specificity for the HIV PRs. A tethered HIVl P R dimer was not inhibited to the same extent as the wild-type enzymes by any of the interface peptides, suggesting that these peptides can only interact effectively with the interface of the two-subunit HIV PR. Measurements of relative dissociation constants by limit dilution of the enzyme show that the one-strand peptide causes a shift in the observed Kd for the HIVl PR. Both one-and two-strand peptides alter the monomer/dimer equilibrium of both HIVl and HIV2 PRs. This was shown by the reduced cross-linking of the HIV2 PR by disuccinimidyl suberate in the presence of the interface peptides. Refolding of the HIVl and H1V2 PRs with the interface peptides shows that only the two-strand peptides prevent the assembly of active PR dimers. Although both one-and two-strand peptides seem to affect dimer dissociation, only the two-strand peptides appear to block assembly. The latter may prove to be more effective backbones for the design of inhibitors directed toward retroviral PR dimerization in vivo.Keywords: aspartyl protease; cross-linking; dimer interface; dissociation; enzyme inhibition; HIVl protease; HIV2 protease; peptide; refolding; tethered dimer Dimerization is required to create a symmetric active site for aspartyl proteases (PRs) encoded by retroviruses. The crystal structures of the human immunodeficiency virus 1 (HIVl) (Navia et al., 1989;Wlodawer et al., 1989) and Rous sarcoma virus (RSV) PRs confirmed the homodimeric nature of these viral enzymes and also defined the regions of interaction between the monomers. The extensive hydrophobic interface present in these PR dimers is dominated by a n antiparallel P-sheet formed by the interdigitation of the N-terminal (residues 1-4 in HIVl and 1-5 in RSV) and the C-terminal (residues 96-99 in HIVl and 119-124 in RSV) 0-strands of each monomer ( Fig. 1 and kinemages). These interactions appear to be a major stabilizing force in the enzyme,

show abstract

“…This part of R2 has an important role in the association with the R1 protein [2][3][4][5][6][7][8][9]. The NMR observable segment also contains the conserved residues, Tyr-356 and Glu-350, that are invariable between species [22].…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that the carboxyl terminal part of protein R2 is important for the binding of protein R2 to protein R1 both in the E. eoli enzyme [24] and in the mammalian and Herpes simplex type I enzymes [5][6][7][8][9]. Truncations of C-terminal residues of protein R2 impair binding of protein R1 [2], and point mutations of conserved residues in the C-terminus reduces or abolishes catalytic activity [34].…”

Section: Introductionmentioning

confidence: 99%

Demonstration of segmental mobility in the functionally essential car☐yl terminal part of ribonucleotide reductase protein R2 from Escherichia coli

Lycksell

Sahlin

1995

FEBS Letters

View full text Add to dashboard Cite

The C-terminus of protein R2 is important for the formation of the enzymatically active complex between proteins R1 and R2 of ribonucleotide reductase from Escherichia coil Some residues in this part of R2 may also be involved in intramolecular electron transfer. We now demonstrate that 26 amino acid residues at C-terminus of protein R2 are mobile in the free protein, and can be studied by aH NMR. Spectral assignment of narrow resonances was made by comparison of TOCSY and NOESY spectra from wild-type R2 with corresponding spectra of a mutant protein R2, lacking 30 residues at the carboxyl terminus.

show abstract

Specific inhibition of herpesvirus ribonucleotide reductase by synthetic peptides

Cited by 211 publications

References 15 publications

Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

Disabling Receptor Ensembles with Rationally Designed Interface Peptidomimetics

Synthetic “interface” peptides alter dimeric assembly of the HIV 1 and 2 proteases

Demonstration of segmental mobility in the functionally essential car☐yl terminal part of ribonucleotide reductase protein R2 from Escherichia coli

Contact Info

Product

Resources

About