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Biomedical subjects

P Beaulieu

Publications and source records attributed to P Beaulieu.

At least 37 records · Page 2Linked to original sources
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

Ureido-based peptidomimetic inhibitor of herpes simplex virus ribonucleotide reductase: an investigation of inhibitor bioactive conformation.

We have been investigating peptidomimetic inhibitors of herpes simplex virus (HSV) ribonucleotide reductase (RR). These inhibitors bind to the HSV RR large subunit and consequently prevent subunit association and subsequent enzymatic activity. This report introduces a new series of compounds that contain an extra nitrogen (a ureido function) at the inhibitor N-terminus. This nitrogen improves inhibitor binding potency 50-fold over our first published inhibitor series. Evidence supports that this improvement in potency results from a new hydrogen-bonding contact between the inhibitor and the RR large subunit. This report also provides evidence for the bioactive conformation around two important amino acid residues contained in our inhibitors. A tert-butyl group, which contributes 100-fold to inhibitor potency but does not directly bind to the large subunit, favors an extended beta-strand conformation that is prevalent in solution and in the bound state. More significantly, the bioactive conformation around a pyrrolidine-modified asparagine residue, which contributes over 30 000-fold to inhibitor potency, is elucidated through a series of conformationally restricted analogues.

Enzyme Inhibitors↗
PubMed1996

Patient-controlled analgesia after spinal fusion for idiopathic scoliosis.

One hundred adolescents undergoing posterior spinal fusion for scoliosis were reviewed to assess the adequacy of postoperative patient-controlled analgesia. There were 94 females and 6 males. The mean settings for morphine dosage were a loading dose of 114.5 micrograms.kg-1, a bolus dose of 24.8 micrograms.kg-1, and a lockout interval of 9.9 minutes. This was used for an average of 75.8 h, with a 52.2% success rate. Adolescents using patient-controlled analgesia showed a great variability in morphine requirements with greater use as they became older. The requirement was not significantly different on the 1st, 2nd and 3rd postoperative days and the total consumption was 52.2 micrograms.kg-1.h-1. Nausea and vomiting occurred in 45% and pruritus in 15%. There were 7 cases of respiratory depression who all recovered promptly and completely. This method is associated with high morphine requirements in adolescents, but can be used safely.

Adolescent↗
PubMed1996

[Incontinentia pigmenti].

Incontinentia pigmenti (IP) is a hereditary syndrome characterized by specific skin lesions occurring mostly during the neonatal period (96% of the cases before 6 weeks of age). These skin lesions have four steps of evolution: inflammatory or erythemato-bullous stage (very often associated with peripheral blood hyper-eosinophilia), proliferative or verruco-lichenoid stage, pigmentary or terminal stage characterized by "fountain" or "firework" features (with a picture of pigmentary incontinence at histological examination), sometimes there is a fourth stage referred to as "involutive". Ocular and neurological involvement is the main determinant in the prognosis. Eye lesions include corneal flecks, cataracts, uveitis or optical atrophy with retrolental fribroplasia. The neurological involvement includes pyramidal syndrome, cerebral ataxia, microcephalia, and mental retardation. The disease has mainly an X-linked dominant transmission and is usually lethal for males. Rare cases are observed in boys, some being associated with Klinefelter syndrome. Research is ongoing to identify the IP gene on the X chromosome. In the family form of IP, the gene has been located on chromosome Xq28, which allows prenatal diagnosis using trophoblast biopsy.

Eye Diseases↗
PubMed1996

Direct chronotropic effects of atrial and C-type natriuretic peptides in anaesthetized dogs.

1. The chronotropic effects of atrial natriuretic peptide (ANP) and C-type natriuretic peptide (CNP) were investigated using injections (50 micrograms in 1 ml of Tyrode solution as bolus over 1 min) directly into the sinus node artery of 21 anaesthetized and vagotomized dogs which had been pretreated with a beta-adrenoceptor antagonist. The injections were also repeated following: (a) alpha-adrenoceptor antagonism (prazosin) and muscarinic receptor antagonism (atropine); (b) inhibition of prostaglandin synthesis (indomethacin); (c) angiotensin II AT1 receptor antagonism (losartan); (d) histamine H1 (mepyramine) and H2 (cimetidine) receptor antagonism. 2. The results obtained indicate that ANP had no significant effect on the basal sinus rate, whereas CNP produced a slight but significant increase of 12 +/- 2 beats min-1. The effect of CNP was long-lasting (return to pre-injection levels after maximum effect in 17 +/- 3 min) and was not influenced by the various antagonists mentioned above. 3. During in vitro experiments on spontaneously beating right atria isolated from 6 dogs, the injection of CNP (50 micrograms in 1 ml of Tyrode solution) into the sinus node artery produced an increase in atrial rate of 14 +/- 1 beats min-1. 4. The results of this work indicate that CNP exerts a significant and prolonged positive chronotropic effect both in vivo and in vitro. Other studies are required to elucidate the mechanism of action of CNP on the heart conduction system, to ascertain the presence of natriuretic peptide receptor B in the region of the sinoatrial node and to determine the role of CNP in the control of heart rate.

Adrenergic beta-Antagonists↗
PubMed1996

Latex anaphylaxis in a myasthenic child undergoing thymectomy.

Anaphylactic shock occurred in a 9-year-old myasthenic boy after induction of anesthesia for thymectomy. Resuscitation was successful. Subsequent skin testing identified latex as the cause. Although the patient was not in a high-risk group for latex allergy, detailed questioning confirmed that sensitivity had developed during repeated exposures in previous anesthesia and dental care. Six months later, after taking steroids and antihistaminic drugs prophylactically and avoiding all latex-containing products, the boy underwent uncomplicated thymectomy. The possibility of latex allergy should be borne in mind when dealing with patients previously exposed to repeated medical care. Adequate, latex-free equipment should be available in operating rooms to deal with patients who are allergic to latex.

Anaphylaxis↗
PubMed1995

Peptidomimetic inhibitors of herpes simplex virus ribonucleotide reductase: a new class of antiviral agents.

We have been investigating a new class of antiviral compounds effective against herpes simplex virus (HSV) in vitro and in vivo. Antiviral activity results from inhibition of HSV ribonucleotide reductase (RR). The inhibitors are designed as mimics of the RR small subunit C-terminus, a region essential for RR subunit association and consequently enzymatic activity. Inhibition results from specific binding of the inhibitor to the HSV RR large subunit thereby preventing subunit association. This report details the structure--activity studies that lead to the indentification of BILD 1263, a potent inhibitor of HSV RR subunit association (IC50, 0.2 nM) that also inhibits the replication of HSV types 1 and 2 in cell culture (EC50, 3 and 4 microM) and reduces the severity of HSV-1-induced keratitis in a murine ocular model. The discovery of inhibitors with in vitro antiviral results from a combination of improving inhibitor potency in a RR binding assay and modifying inhibitor physicochemical properties. The importance and possible role of the new structural modifications introduced into this inhibitor series is discussed.

Animals↗
PubMed1995

Crystal structures of HIV-2 protease in complex with inhibitors containing the hydroxyethylamine dipeptide isostere.

BACKGROUND: The HIV protease is essential for the life cycle of the virus and is an important target for the development of therapeutic treatments against AIDS. The structures of HIV protease in complex with different inhibitors have helped in understanding the interactions between inhibitors and the protease and in the design and optimization of HIV protease inhibitors. RESULTS: We report here crystal structures at up to 1.7 A resolution of the homodimeric HIV-2 protease in complex with seven inhibitors containing the hydroxyethylamine dipeptide isostere. A novel dimethylphenoxyacetyl group that is present in some of these inhibitors is inserted between residues 48' and 49' in the flap of the protease and residues 29' and 30' (where a prime indicates a residue in the second monomer), which undergo a conformational change to accommodate the phenyl ring of the inhibitor. CONCLUSIONS: This study shows that besides the residues in the flap and residues 79-81 in the S1 substrate-binding pocket which undergo conformational changes upon inhibitor binding, residues 29 and 30 can also adapt their conformation to fit certain inhibitors. Conformational flexibility of the HIV protease plays an important role in inhibitor binding.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Blood lactate levels of decathletes during competition.

There are many detailed physiological profiles of athletes who participate in a wide variety of sporting activities but few data have been obtained on decathletes. This study defines some physiological characteristics of these athletes and measures capillary lactate concentrations [La(b)] during a laboratory test of progressive maximal exhaustion and the different events during competition. The treadmill test is similar to the 100 m, 400 m and 1500 m in terms of [La(b)] accumulation but only similar to the 1500 m in terms of velocity. The 400 m is the most demanding event with the greatest blood lactate accumulation (mean(s.d.) 16.38(2.36) mmol l-1). The [La(b)] at the end of the 110 m hurdles is significantly lower than in any other racing events (mean(s.d.) 6.96(1.32) mmol l-1) compared with mean(s.d.) 12.14(2.87) and mean(s.d.) 11.44(2.16) for the 100 m and 1500 m respectively. The [La(b)] after the long jump, the high jump and the pole vault are not significantly different (mean(s.d.) 5.30(2.23), 4.64(1.39) and 5.36(1.34) mmol l-1) respectively).

Adolescent↗
PubMed1995

Longitudinal melanonychia induced by hydroxyurea: four case reports and review of the literature.

Although the occurrence of skin lesions during long-term hydroxyurea therapy is well known, longitudinal melanonychia (LM) are more rarely described. In the present paper, we report four cases of LM associated with skin lesions induced by long-term daily hydroxyurea therapy (4 to 10 years), characterized by two uncommon aspects: late onset (2.5 to 5 years) and predominance of toenail involvement in three cases.

Adult↗
PubMed1994

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

Herpes simplex viruses (HSV) types 1 and 2 encode their own ribonucleotide reductases (RNRs) (EC 1.17.4.1) to convert ribonucleoside diphosphates into the corresponding deoxyribonucleotides. Like other iron-dependent RNRs, the viral enzyme is formed by the reversible association of two distinct homodimeric subunits. The carboxy terminus of the RNR small subunit (R2) is critical for subunit association and synthetic peptides containing these amino-acid sequences selectively inhibit the viral enzyme by preventing subunit association. Increasing evidence indicates that the HSV RNR is important for virulence and reactivation from latency. Previously, we reported on the design of HSV RNR inhibitors with enhanced inhibitory potency in vitro. We now report on BILD 1263, which to our knowledge is the first HSV RNR subunit-association inhibitor with antiviral activity in vivo. This compound suppresses the replication of HSV-1, HSV-2 and acyclovir-resistant HSV strains in cell culture, and also strongly potentiates the antiviral activity of acyclovir. Most importantly, its anti-herpetic activity is shown in a murine ocular model of HSV-1-induced keratitis, providing an example of potent nonsubstrate-based antiviral agents that prevent protein-protein interactions. The unique antiviral properties of BILD 1263 may lead to the design of new strategies to treat herpesvirus infections in humans.

Amino Acid Sequence↗
PubMed1994

Purification, characterization, and localization of subunit interaction area of recombinant mouse ribonucleotide reductase R1 subunit.

Mammalian ribonucleotide reductase is a heterotetramer formed by the two non-identical homodimers proteins R1 and R2. We have succeeded in expressing the 90-kDa mouse R1 protein in Escherichia coli in an active, soluble form using the T7 RNA polymerase pET vector system. To avoid inclusion bodies, the bacteria were grown at 15 degrees C with minimal concentration of the inducer isopropyl-1-thio-beta-D-galactopyranoside. After a rapid purification procedure, approximately 20 mg of pure R1 protein were obtained per liter of bacterial culture. The concentrated R1 protein solution had a pinkish red color. Spectroscopy in combination with iron and labile sulfur analyses demonstrated that the color originated from an iron-sulfur complex. However, all attempts to demonstrate a function of this complex have been inconclusive. A comparison of the recombinant R1 protein with the corresponding protein purified from calf thymus showed no evidence for glycosylation. Circular dichroism spectroscopy indicated an alpha-helical content of 50%. A flexible COOH-terminal tail of 7 residues in the R2 protein was earlier shown to be essential for binding to the R1 protein. Using a peptide protection assay and photoaffinity labeling, we now show that the R2 protein tail interacts with a region close to the carboxyl terminus of the R1 protein.

Affinity Labels↗
PubMed1994

Contrast induced myocardial signal reduction: effect of lanthanide chelates on ultra high speed MR images.

The myocardial MR signal reduction associated with an intravenous bolus of Gd-DTPA and Dy-DTPA was studied in a canine model. Imaging was performed with a high speed echo-planar type imaging system (Instascan, Advanced NMR Systems, Inc.). Gated spin-echo images were obtained with TE of 30 ms, which permits image acquisition in approximately 40 ms. The gated TR was dependent on the heart rate, with an average TR of 2.4 s. After 0.1 mmol/kg of contrast was injected, 70 images were acquired, which showed in an 80-image data set a reduction in myocardial signal with a gradual return to normal. After dipyridamole infusion, the signal loss was significantly more pronounced, and earlier than in the control data set. There was no significant difference between Gd-DTPA and Dy-DTPA in these imaging studies despite the theoretical prediction of better Dy signal reduction, possibly due to physiological variability during the course of a study or between studies. The cause of enhanced contrast effect after dipyridamole infusion is discussed, as is the basis for dipyridamole enhancement, and the possible role of contrast enhanced MR imaging in the detection of cardiac disease.

Animals↗