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Biomedical subjects

M Poirier

Publications and source records attributed to M Poirier.

At least 19 recordsLinked to original sources
PubMed1999

Ligands for the tyrosine kinase p56lck SH2 domain: discovery of potent dipeptide derivatives with monocharged, nonhydrolyzable phosphate replacements.

p56lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56lck SH2 domain, we have designed novel dipeptides that contain monocharged, nonhydrolyzable phosphate group replacements and bind to the protein with KD's in the low micromolar range. Replacement of the phosphate group in phosphotyrosine-containing sequences by a (R/S)-hydroxyacetic (compound 8) or an oxamic acid (compound 10) moiety leads to hydrolytically stable, monocharged ligands, with 83- and 233-fold decreases in potency, respectively. This loss in binding affinity can be partially compensated for by incorporating large lipophilic groups at the inhibitor N-terminus. These groups provide up to 13-fold increases in potency depending on the nature of the phosphate replacement. The discovery of potent (2-3 microM), hydrolytically stable dipeptide derivatives, bearing only two charges at physiological pH, represents a significant step toward the discovery of compounds with cellular activity and the development of novel therapeutics for conditions associated with undesired T-cell proliferation.

Crystallography, X-Ray↗
PubMed1999

Phosphotyrosine-containing dipeptides as high-affinity ligands for the p56lck SH2 domain.

Src homology-2 (SH2) domains are noncatalytic motifs containing approximately 100 amino acid residues that are involved in intracellular signal transduction. The phosphotyrosine-containing tetrapeptide Ac-pYEEI binds to the SH2 domain of p56lck (Lck) with an affinity of 0.1 microM. Starting from Ac-pYEEI, we have designed potent antagonists of the Lck SH2 domain which are reduced in peptidic character and in which the three carboxyl groups have been eliminated. The two C-terminal amino acids (EI) have been replaced by benzylamine derivatives and the pY + 1 glutamic acid has been substituted with leucine. The best C-terminal fragment identified, (S)-1-(4-isopropylphenyl)ethylamine, binds to the Lck SH2 domain better than the C-terminal dipeptide EI. Molecular modeling suggests that the substituents at the 4-position of the phenyl ring occupy the pY + 3 lipophilic pocket in the SH2 domain originally occupied by the isoleucine side chain. This new series of phosphotyrosine-containing dipeptides binds to the Lck SH2 domain with potencies comparable to that of tetrapeptide 1.

Binding, Competitive↗
PubMed1998

Studies on the C-terminal of hexapeptide inhibitors of the hepatitis C virus serine protease.

Replacement of the C-terminal carboxylic acid functionality of peptide inhibitors of hepatitis C virus (HCV) NS3 protease (complexed with NS4A peptide cofactor) by activated carbonyl groups does not produce any substantial increase in potency. These latter inhibitors also inhibit a variety of other serine and cysteine proteases whereas the carboxylic acids are specific. Norvaline was identified as a chemically stable replacement for the P1 residue of Ac-DDIVPC-OH which was also compatible with activated carbonyl functionalities.

Cysteine↗
PubMed1998

New susceptibility locus for rheumatoid arthritis suggested by a genome-wide linkage study.

Rheumatoid arthritis (RA), the most common autoimmune disease, is associated in families with other autoimmune diseases, including insulin-dependent diabetes mellitus (IDDM). Its genetic component has been suggested by familial aggregation (lambdas = 5), twin studies, and segregation analysis. HLA, which is the only susceptibility locus known, has been estimated to account for one-third of this component. The aim of this paper was to identify new RA loci. A genome scan was performed with 114 European Caucasian RA sib pairs from 97 nuclear families. Linkage was significant only for HLA (P < 2.5.10(-5)) and nominal for 19 markers in 14 other regions (P < 0.05). Four of the loci implicated in IDDM potentially overlap with these regions: the putative IDDM6, IDDM9, IDDM13, and DXS998 loci. The first two of these candidate regions, defined in the RA genome scan by the markers D18S68-D18S61-D18S469 (18q22-23) and D3S1267 (3q13), respectively, were studied in 194 additional RA sib pairs from 164 nuclear families. Support for linkage to chromosome 3 only was extended significantly (P = 0.002). The analysis of all 261 families provided a linkage evidence of P = 0. 001 and suggested an interaction between this putative RA locus and HLA. This locus could account for 16% of the genetic component of RA. Candidate genes include those coding for CD80 and CD86, molecules involved in antigen-specific T cell recognition. In conclusion, this first genome scan in RA Caucasian families revealed 14 candidate regions, one of which was supported further by the study of a second set of families.

Arthritis, Rheumatoid↗
PubMed1998

Peptide-based inhibitors of the hepatitis C virus serine protease.

Hexapeptide DDIVPC-OH is a competitive inhibitor of the hepatitis C virus (HCV) NS3 protease complexed with NS4A cofactor peptide. This hexapeptide corresponds to the N-terminal cleavage product of an HCV dodecapeptide substrate derived from the NS5A/5B cleavage site. Structure-activity studies on Ac-DDIVPC-OH revealed that side chains of the P4, P3 and P1 residues contribute the most to binding and that the introduction of a D-amino acid at the P5 position improves potency considerably. Furthermore, there is a strong preference for cysteine at the P1 position and conservative replacements, such as serine, are not well tolerated.

Amino Acid Sequence↗
PubMed1998

Role of the striatum, cerebellum and frontal lobes in the automatization of a repeated visuomotor sequence of movements.

Recently, Doyon et al. [20] demonstrated that lesions to both the striatum and to the cerebellum in humans produce a similar deficit in the learning of a repeated visuomotor sequence, which occurs late in the acquisition process. We now report the results of two experiments that were designed to examine whether this impairment was due to a lack of automatization of the repeating sequence of finger movements by using a dual-task paradigm and by testing for long-term retention of this skill. In Experiment 1, the performance of groups of patients with Parkinson's disease, or with damage to the cerebellum or to the frontal lobes, was compared to that of matched control subjects on the Repeated Sequence Test (primary task) and the Brooks' Matrices Test (secondary task). These two tests were administered concomitantly in both early and late learning phases of the visuomotor sequence. Overall, the groups did not differ in their ability to execute the primary task. By contrast, in accordance with the predictions, patients in Stages 2-3 of Parkinson's disease or with a cerebellar lesion failed to reveal the expected increase in performance on the secondary task seen with learning, suggesting that the latter groups of patients did not have access to the same level of residual cognitive resources to complete the matrices compared to controls. In Experiment 2, the same groups of patients and control subjects were retested again 10-18 months later. They were given four blocks of 100 trials each of the repeating sequence task, followed by a questionnaire and a self-generation task that measured their declarative knowledge of that sequence. The results revealed a long-term retention impairment only in patients who changed from Stage I to Stage II of the disease (suggesting further striatal degeneration) during the one-year interval, or who had a cerebellar lesion. By contrast, performance of the three clinical groups did not differ from controls on declarative memory tests. These findings suggest that both the striatum and the cerebellum participate to the automatization process during the late (slow) learning stage of a sequence of finger movements and that these structures also play a role in the neuronal mechanism subserving long-term retention of such a motor sequence behavior.

Adult↗
PubMed1997

Peptidomimetic inhibitors of the human cytomegalovirus protease.

The development of peptidomimetic inhibitors of the human cytomegalovirus (HCMV) protease showing sub-micromolar potency in an enzymatic assay is described. Selective substitution of the amino acid residues of these inhibitors led to the identification of tripeptide inhibitors showing improvements in inhibitor potency of 27-fold relative to inhibitor 39 based upon the natural tetrapeptide sequence. Small side chains at P1 were well tolerated by this enzyme, a fact consistent with previous observations. The S2 binding pocket of HCMV protease was very permissive, tolerating lipophilic and basic residues. The substitutions tried at P3 indicated that a small increase in inhibitor potency could be realized by the substitution of a tert-leucine residue for valine. Substitutions of the N-terminal capping group did not significantly affect inhibitor potency. Pentafluoroethyl ketones, alpha,alpha-difluoro-beta-keto amides, phosphonates and alpha-keto amides were all effective substitutions for the activated carbonyl component and gave inhibitors which were selective for HCMV protease. A slight increase in potency was observed by lengthening the P1' residue of the alpha-keto amide series of inhibitors. This position also tolerated a variety of groups making this a potential site for future modifications which could modulate the physicochemical properties of these molecules.

Antiviral Agents↗
PubMed1997

Effects and metabolism of fumarate in the perfused rat heart. A 13C mass isotopomer study.

The cardioprotective effects of fumarate have been linked to its metabolism to succinate through both oxidative and reductive pathways. To date, the relative contribution of these pathways is a subject of controversy. To address this question, we designed a protocol with 13C substrates and took advantage of 13C isotopomer analysis by gas chromatography-mass spectrometry. Rat hearts were perfused with 11 mM glucose, 1 mM lactate, 0.2 mM pyruvate, 0.2 mM [1-13C]octanoate, and 0.04 or 0.4 mM [U-13C4]fumarate. On reoxygenation after 40 min of severe hypoxia, hearts perfused with 0.4 mM fumarate showed a better recovery of contractile function and released less lactate dehydrogenase (an index of cellular necrosis) than those perfused with 0.04 mM fumarate. The 13C data showed that, in hypoxic hearts, fumarate conversion to succinate occurred only through reduction, although it accounted for only 16% of total succinate release. Most of the succinate was formed through the oxidation of alpha-ketoglutarate or its precursors (50 +/- 5%) and by another yet-unidentified pathway (34 +/- 4%). These data show that, in a model of hypoxia-reoxygenation, the cardioprotective effects of fumarate were associated with its predominant metabolism to succinate through the reductive pathway.

Animals↗
PubMed1997

The influence of word function in the missing-letter effect: further evidence from French.

When asked to detect target letters while reading continuous text, subjects miss more letters in highly common function words than in less common content words. This is known as the missing-letter effect. According to the structural account, the higher omission rates for frequent function words are attributable to their role in supporting the extraction of phrase structure, after which they become lost in the transition from structure to meaning. This implies that word function in and of itself should affect letter detection accuracy. This issue was examined in four experiments while controlling for a number of confounded factors associated with another influential model: the unitization account. The first experiment extended the missing-letter effect to the French language. The second showed that letter detection is influenced by slight variations in the function assumed by the same word, such as when it is used as a definite article as opposed to a pronoun. This effect was observed even when the frequency of the orthographic pattern and the syllable stress patterns were controlled. In the last two experiments, a control was added for another factor: frequency of word meaning. The results indicate that word function contributes to the missing-letter effect over and above what is contributed by frequency of word meaning.

Adult↗
PubMed1996

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase with improved in vivo antiviral activity.

We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work. Structure-activity studies reveal beneficial modifications that result in improved antiviral potency in cell culture in a murine ocular model of HSV-induced keratitis. These modifications include a stereochemically defined (2,6-dimethylcyclohexyl)amino N-terminus, two ketomethylene amide bond isosteres, and a (1-ethylneopentyl)amino C-terminus. These three modifications led to the preparation of BILD 1351, our most potent antiherpetic agent containing a ureido N-terminus. Incorporation of the C-terminal modification into our inhibitor series based on a (phenylpropionyl)valine N-terminus provided BILD 1357, a significantly more potent antiviral compound than our previously published best compound, BILD 1263.

Animals↗
PubMed1996

Immediate serial recall, word frequency, item identity and item position.

Eighteen subjects completed an immediate serial recall task, where the to-be-recalled lists consisted of either high, medium, or low-frequency items. Moreover, lists were either phonologically similar or distinct. Results showed that increasing frequency enhanced item information recall but had no effect on order recall. Conversely, increasing phonological similarity had a detrimental effect on order recall but no significant effect on item recall. It is argued that both effects reflect retrieval processes where degraded representations are reconstructed on the basis of long-term knowledge: Low-frequency words have reduced accessibility, lowering the probability of correct reconstruction, and phonologically similar items are more easily confused with other recall candidates.

Adult↗