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Overview

ABSTRACT Ribosome binding to eukaryotic mRNA is a multistep process which is mediated by the cap structure [m 7 G(5′)ppp(5′)N, where N is any nucleotide] present at the 5′ termini of all cellular (with the exception of organellar) mRNAs. The heterotrimeric complex, eukaryotic initiation factor 4F (eIF4F), interacts directly with the cap structure via the eIF4E subunit and functions to assemble a ribosomal initiation complex on the mRNA. In mammalian cells, eIF4E activity is regulated in part by three related translational repressors (4E-BPs), which bind to eIF4E directly and preclude the assembly of eIF4F. No structural counterpart to 4E-BPs exists in the budding yeast, Saccharomyces cerevisiae . However, a functional homolog (named p20) has been described which blocks cap-dependent translation by a mechanism analogous to that of 4E-BPs. We report here on the characterization of a novel yeast eIF4E-associated protein (Eap1p) which can also regulate translation through binding to eIF4E. Eap1p shares limited homology to p20 in a region which contains the canonical eIF4E-binding motif. Deletion of this domain or point mutation abolishes the interaction of Eap1p with eIF4E. Eap1p competes with eIF4G (the large subunit of the cap-binding complex, eIF4F) and p20 for binding to eIF4E in vivo and inhibits cap-dependent translation in vitro. Targeted disruption of the EAP1 gene results in a temperature-sensitive phenotype and also confers partial resistance to growth inhibition by rapamycin. These data indicate that Eap1p plays a role in cell growth and implicates this protein in the TOR signaling cascade of S. cerevisiae .

16 Oct 1998·Angewandte Chemie International EditionQ1 · CHEMISTRY

The Conformation of a Peptidyl Methyl Ketone Inhibitor Bound to the Human Cytomegalovirus Protease

Q1 · CHEMISTRY

Article

Author: Bonneau, Pierre R ; Ogilvie, William W ; Déziel, Robert ; Kawai, Stephen H ; Grand-Maître, Chantal ; LaPlante, Steven R ; Aubry, Norman ; Cameron, Dale R

A weak inhibitor means faster exchange! Since the methyl ketone MK2 is a weak noncovalent peptidyl inhibitor of the human cytomegalovirus protease, exchange between the free and enzyme-bound forms is rapid. This allows for the use of transferred NOE NMR methods and molecular modeling, which show that the bound conformation of MK2 is an extended peptide. This is confirmed by the results of an X-ray crystallographic analysis of a related enzyme-inhibitor complex.

01 Oct 1998·Antiviral Chemistry and Chemotherapy

Potent β-Lactam Inhibitors of Human Cytomegalovirus Protease

Article

Author: Déziel, R ; Haché, B ; Yoakim, C ; Plante, R ; Grand-Maître, C ; Cameron, DR ; Naud, J ; Guse, I ; Kawai, S ; Chabot, C ; Ogilvie, WW ; O'Meara, JA

A series of novel monobactam inhibitors of human cytomegalovirus (HCMV) protease has been described that possess a heterocyclic thiomethyl side chain at C-4. Changes to the heterocycle did not significantly change the inhibitory activity of these compounds in an enzymatic assay, although improvements in solubility and cell culture activity were noted. A number of permutations between C-4 substitutions and N-1 derivatives led to the identification of several β-lactams with antiviral activity in a plaque reduction assay. N-methyl thiotetrazole-containing compounds were found to be the most potent inhibitors in the enzymatic assay.

100 Deals associated with Bio-Méga Research Division

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100 Translational Medicine associated with Bio-Méga Research Division

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Pipeline

Pipeline Snapshot as of 14 Nov 2024

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

BILD-1263 ( HSV RNR )	Keratitis More	Discontinued
BILD-1351	Herpes Simplex More	Discontinued
BILD-1357 ( HSV RNR )	Herpes Simplex More	Discontinued
VZV inhibitors(BioMega/Boehringer Ingelheim)	Varicella Zoster Virus Infection More	Discontinued
BILD-1633-SE	Herpes Simplex More	Pending