scholarly journals Dissection of the Structural Features of a Fungicidal Antibody-Derived Peptide

2018 ◽  
Vol 19 (12) ◽  
pp. 3792 ◽  
Author(s):  
Thelma A. Pertinhez ◽  
Tecla Ciociola ◽  
Laura Giovati ◽  
Walter Magliani ◽  
Silvana Belletti ◽  
...  
Keyword(s):  
Critical Role ◽  
Multidrug Resistant ◽  
Structural Features ◽  
Coupling Constants ◽  
Random Coil ◽  
Significant Activity ◽  
Cd Spectra ◽  
Negative Band ◽  
Polyproline Ii

The synthetic peptide T11F (TCRVDHRGLTF), derived from the constant region of human IgM antibodies, proved to exert a significant activity in vitro against yeast strains, including multidrug resistant isolates. Alanine substitution of positively charged residues led to a decrease in candidacidal activity. A more dramatic reduction in activity resulted from cysteine replacement. Here, we investigated the conformational properties of T11F and its alanine-substituted derivatives by circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy. Peptide interaction with Candida albicans cells was studied by confocal and scanning electron microscopy. T11F and most of its derivatives exhibited CD spectra with a negative band around 200 nm and a weaker positive band around 218 nm suggesting, together with NMR coupling constants, the presence of a polyproline II (PPII) helix, a conformational motif involved in a number of biological functions. Analysis of CD spectra revealed a critical role for phenylalanine in preserving the PPII helix. In fact, only the F11A derivative presented a random coil conformation. Interestingly, the loss of secondary structure influenced the rate of killing, which turned out to be significantly reduced. Overall, the obtained results suggest that the PPII conformation contributes in characterising the cell penetrating and fungicidal properties of the investigated peptides.

scholarly journals A New Strategy for Glioblastoma Treatment: In Vitro and In Vivo Preclinical Characterization of Si306, a Pyrazolo[3,4-d]Pyrimidine Dual Src/P-Glycoprotein Inhibitor

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 848 ◽  
Author(s):  
Anna Lucia Fallacara ◽  
Claudio Zamperini ◽  
Ana Podolski-Renić ◽  
Jelena Dinić ◽  
Tijana Stanković ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Multidrug Resistant ◽  
Cellular Level ◽  
Cns Tumors ◽  
Significant Activity ◽  
Src Tyrosine Kinase ◽  
P Glycoprotein ◽  
New Strategy

Overexpression of P-glycoprotein (P-gp) and other ATP-binding cassette (ABC) transporters in multidrug resistant (MDR) cancer cells is responsible for the reduction of intracellular drug accumulation, thus decreasing the efficacy of chemotherapeutics. P-gp is also found at endothelial cells’ membrane of the blood-brain barrier, where it limits drug delivery to central nervous system (CNS) tumors. We have previously developed a set of pyrazolo[3,4-d]pyrimidines and their prodrugs as novel Src tyrosine kinase inhibitors (TKIs), showing a significant activity against CNS tumors in in vivo. Here we investigated the interaction of the most promising pair of drug/prodrug with P-gp at the cellular level. The tested compounds were found to increase the intracellular accumulation of Rho 123, and to enhance the efficacy of paclitaxel in P-gp overexpressing cells. Encouraging pharmacokinetics properties and tolerability in vivo were also observed. Our findings revealed a novel role of pyrazolo[3,4-d]pyrimidines which may be useful for developing a new effective therapy in MDR cancer treatment, particularly against glioblastoma.

scholarly journals In Vitro Activities of RWJ-54428 (MC-02,479) against Multiresistant Gram-Positive Bacteria

2001 ◽  
Vol 45 (5) ◽  
pp. 1422-1430 ◽  
Author(s):  
Suzanne Chamberland ◽  
Johanne Blais ◽  
Monica Hoang ◽  
Cynthia Dinh ◽  
Dylan Cotter ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Penicillin G ◽  
Significant Activity ◽  
Coagulase Negative Staphylococci ◽  
Gram Positive ◽  
Gram Positive Bacteria ◽  
Level Of Activity ◽  
Resistant Strains ◽  
High Level

ABSTRACT RWJ-54428 (MC-02,479) is a new cephalosporin with a high level of activity against gram-positive bacteria. In a broth microdilution susceptibility test against methicillin-resistant Staphylococcus aureus (MRSA), RWJ-54428 was as active as vancomycin, with an MIC at which 90% of isolates are inhibited (MIC90) of 2 μg/ml. For coagulase-negative staphylococci, RWJ-54428 was 32 times more active than imipenem, with an MIC90 of 2 μg/ml. RWJ-54428 was active against S. aureus, Staphylococcus epidermidis, and Staphylococcus haemolyticus isolates with reduced susceptibility to glycopeptides (RWJ-54428 MIC range, ≤0.0625 to 1 μg/ml). RWJ-54428 was eight times more potent than methicillin and cefotaxime against methicillin-susceptible S. aureus (MIC90, 0.5 μg/ml). For ampicillin-susceptible Enterococcus faecalis (including vancomycin-resistant and high-level aminoglycoside-resistant strains), RWJ-54428 had an MIC90 of 0.125 μg/ml. RWJ-54428 was also active against Enterococcus faecium, including vancomycin-, gentamicin-, and ciprofloxacin-resistant strains. The potency against enterococci correlated with ampicillin susceptibility; RWJ-54428 MICs ranged between ≤0.0625 and 1 μg/ml for ampicillin-susceptible strains and 0.125 and 8 μg/ml for ampicillin-resistant strains. RWJ-54428 was more active than penicillin G and cefotaxime against penicillin-resistant, -intermediate, and -susceptible strains ofStreptococcus pneumoniae (MIC90s, 0.25, 0.125, and ≤0.0625 μg/ml, respectively). RWJ-54428 was only marginally active against most gram-negative bacteria; however, significant activity was observed against Haemophilus influenzae andMoraxella catarrhalis (MIC90s, 0.25 and 0.5 μg/ml, respectively). This survey of the susceptibilities of more than 1,000 multidrug-resistant gram-positive isolates to RWJ-54428 indicates that this new cephalosporin has the potential to be useful in the treatment of infections due to gram-positive bacteria, including strains resistant to currently available antimicrobials.

scholarly journals Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

2012 ◽  
Vol 56 (7) ◽  
pp. 3475-3480 ◽  
Author(s):  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
Jane Xu Kelly ◽  
Yuexin Li ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Plasmodium Yoelii ◽  
Significant Activity ◽  
Drug Resistant ◽  
Content Type ◽  
Resistant Strains ◽  
Drug Resistant Strains ◽  
Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

Development of Hepcidin Agonists and Antagonists.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. SCI-27-SCI-27
Author(s):  
Elizabeta Nemeth
Keyword(s):  
Rational Design ◽  
Hereditary Hemochromatosis ◽  
Structural Features ◽  
Deficiency Anemia ◽  
Beta Thalassemia ◽  
Significant Activity ◽  
Advisory Committees ◽  
Rare Type

Abstract Abstract SCI-27 Hepcidin binding to its receptor, the iron exporter ferroportin, leads to degradation of the ligand-receptor complex and decreased flow of iron into plasma from duodenum, macrophages and hepatocytes. Dysregulated production of hepcidin or its aberrant interaction with ferroportin causes a number of iron disorders. Hepcidin deficiency, either relative or absolute, underlies excessive iron loading in hereditary hemochromatosis, beta-thalassemia and hepatitis C. A rare type of hereditary hemochromatosis is also caused by ferroportin resistance to hepcidin. On the other side of the spectrum, hepcidin excess causes iron restriction and anemia, as is observed in patients with iron-refractory iron deficiency anemia. Hepcidin also contributes to development of anemia in different inflammatory disorders and chronic kidney disease, and may cause erythropoietin resistance. Hepcidin agonist and antagonists thus may be useful for treatment of different iron disorders. Antagonist strategies for lowering hepcidin levels have been reported, and include hepcidin-neutralizing monoclonal antibodies or agents interfering with the BMP-related hepcidin production (soluble hemojuvelin and dorsomorphin). To undertake the rational design of drug leads, we analyzed the critical structural features that determine the interaction of hepcidin and Fpn. We showed that the thiol form of Fpn residue Cys326 is essential for hepcidin binding, as is the presence of a disulfide bond on hepcidin. The mechanism of binding appears to involve disulfide exchange between the two molecules. Treatment of ferroportin-expressing cells with thiol-reactive agents prevented hepcidin binding and allowed continuous export of iron from cells. Systematic mutagenesis of additional residues on hepcidin showed that His3, Phe4 and Phe9 are also important for binding to ferroportin. To provide leads for hepcidin agonists, we then synthesized a mini-hepcidin containing only the 9 N-terminal hepcidin residues (DTHFPICIF), and showed that it displayed significant activity in vitro. Proteolysis-resistant analogs of this peptide were also active in vivo after intraperitoneal injection in mice. The small size of these peptides may allow oral bioavailability. Understanding the mechanisms of hepcidin regulation and its interaction with ferroportin will facilitate the development of new agents for the treatment of iron overload disorders and iron-restricted anemias. Disclosures Nemeth: Intrinsic LifeSciences: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Exploration of 2, 4-diaminopyrimidine and 2, 4-diamino-s-triazine derivatives as potential antifilarial agents

Parasitology ◽  
2013 ◽  
Vol 140 (8) ◽  
pp. 959-965 ◽  
Author(s):  
R. D. SHARMA ◽  
S. BAG ◽  
N. R. TAWARI ◽  
M. S. DEGANI ◽  
K. GOSWAMI ◽  
...  
Keyword(s):  
Folic Acid ◽  
Folinic Acid ◽  
Neglected Tropical Diseases ◽  
Structural Features ◽  
Biological Evaluation ◽  
World Health ◽  
Parp Inhibition ◽  
Significant Activity ◽  
Acridine Orange Staining

SUMMARYIn view of the mandate from the World Health Organization (WHO) for developing novel drug candidates against human lymphatic filariasis, dihydrofolate reductase (DHFR) inhibitors are explored as potential antifilarial agents. The in vitro biological evaluation of an in-house library of 12 diverse antifolate compounds with 2,4-diaminopyrimidine and 2,4-diamino-s-triazine structural features against Brugia malayi is reported. To confirm the DHFR inhibitory potential of these compounds, reversal studies using folic acid and folinic acid were undertaken. Inhibition of DHFR can induce apoptosis; in this light, preliminary evidence of apoptosis by test compounds was detected using ethidium bromide–acridine orange staining and the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibition assay. Among the evaluated compounds, 3 showed significant activity against both microfilariae and adult worms. The effects of 2 of these compounds were mostly reversed by folic acid, validating DHFR inhibitory activity. Partial reversal of the effect of 2 compounds by folinic acid and non-reversal of the effect of the third compound both by folic and folinic acids are discussed. This study opens new avenues for the discovery of lead molecules by exploiting the folate pathway against one of the major neglected tropical diseases, filariasis.

scholarly journals Preclinical Testing of the Nitroimidazopyran PA-824 for Activity against Mycobacterium tuberculosis in a Series of In Vitro and In Vivo Models

2005 ◽  
Vol 49 (6) ◽  
pp. 2294-2301 ◽  
Author(s):  
Anne J. Lenaerts ◽  
Veronica Gruppo ◽  
Karen S. Marietta ◽  
Christine M. Johnson ◽  
Diane K. Driscoll ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Infection Model ◽  
Significant Activity ◽  
Dependent Manner ◽  
In Vivo Models ◽  
Long Term Treatment

ABSTRACT This study extends earlier reports regarding the in vitro and in vivo efficacies of the nitroimidazopyran PA-824 against Mycobacterium tuberculosis. PA-824 was tested in vitro against a broad panel of multidrug-resistant clinical isolates and was found to be highly active against all isolates (MIC < 1 μg/ml). The activity of PA-824 against M. tuberculosis was also assessed grown under conditions of oxygen depletion. PA-824 showed significant activity at 2, 10, and 50 μg/ml, similar to that of metronidazole, in a dose-dependent manner. In a short-course mouse infection model, the efficacy of PA-824 at 50, 100, and 300 mg/kg of body weight formulated in methylcellulose or cyclodextrin/lecithin after nine oral treatments was compared with those of isoniazid, rifampin, and moxifloxacin. PA-824 at 100 mg/kg in cyclodextrin/lecithin was as active as moxifloxacin at 100 mg/kg and isoniazid at 25 mg/kg and was slightly more active than rifampin at 20 mg/kg. Long-term treatment with PA-824 at 100 mg/kg in cyclodextrin/lecithin reduced the bacterial load below 500 CFU in the lungs and spleen. No significant differences in activity between PA-824 and the other single drug treatments tested (isoniazid at 25 mg/kg, rifampin at 10 mg/kg, gatifloxacin at 100 mg/kg, and moxifloxacin at 100 mg/kg) could be observed. In summary, its good activity in in vivo models, as well as its activity against multidrug-resistant M. tuberculosis and against M. tuberculosis isolates in a potentially latent state, makes PA-824 an attractive drug candidate for the therapy of tuberculosis. These data indicate that there is significant potential for effective oral delivery of PA-824 for the treatment of tuberculosis.

Molecular Design and Synthesis of New 3,4-Dihydropyrimidin-2(1H)-Ones as Potential Anticancer Agents with VEGFR-2 Inhibiting Activity

2019 ◽  
Vol 19 (3) ◽  
pp. 310-322
Author(s):  
Amany S. Mostafa ◽  
Waleed A. Bayoumi ◽  
Mohamed El-Mesery ◽  
Abdelaziz Elgaml
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Molecular Design ◽  
Growth Factor Receptor ◽  
Docking Study ◽  
Structural Features ◽  
Significant Activity ◽  
Inhibiting Activity ◽  
Molecular Docking Study

Background: Two series of 3,4-dihydropyrimidin-2(1H)-one derivatives were designed based on the main structural features characterizing reported anticancer compounds with potent VEGFR-2 inhibiting activity. Methods: All the target compounds were synthesized and investigated for their in vitro anticancer activity using MTT assay and NCI protocol. The most active compounds were further investigated for the VEGFR-2 inhibiting activity using enzyme inhibition assay. Results: Of these derivatives, compound 8b possessed significant activity against Caco-2 (IC50 of 24.9 µM) and MCF7 (IC50 of 29.4 µM), compound 10 showed excellent potency against HCT-116 (IC50 of 32.6 µM), HEPG2 (IC50 of 16.4 µM) and MCF7 (IC50 of 32.8 µM), while compound 11b exhibited moderate anticancer activity towards MCF7 (IC50 of 41.7µM). Both 8b and 10 exhibited good potency regarding the inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), with an IC50 of 14.00 and 21.62 nM, respectively. Conclusion: The activity was rationalized based on molecular docking study that supported their VEGFR-2 inhibitory activity; as indicated by their favorable binding with the active site.

Some Structural Features of Metaphase Chromosomes of Mice and Men

1967 ◽  
Vol 25 ◽  
pp. 190-191
Author(s):  
Godfrey C. Hoskins ◽  
Betty B. Hoskins
Keyword(s):  
Electron Microscopy ◽  
Electron Micrographs ◽  
Structural Features ◽  
Metaphase Chromosomes ◽  
The Future ◽  
Of Mice And Men ◽  
Mouse Cells ◽  
Human And Mouse

Metaphase chromosomes from human and mouse cells in vitro are isolated by micrurgy, fixed, and placed on grids for electron microscopy. Interpretations of electron micrographs by current methods indicate the following structural features.Chromosomal spindle fibrils about 200Å thick form fascicles about 600Å thick, wrapped by dense spiraling fibrils (DSF) less than 100Å thick as they near the kinomere. Such a fascicle joins the future daughter kinomere of each metaphase chromatid with those of adjacent non-homologous chromatids to either side. Thus, four fascicles (SF, 1-4) attach to each metaphase kinomere (K). It is thought that fascicles extend from the kinomere poleward, fray out to let chromosomal fibrils act as traction fibrils against polar fibrils, then regroup to join the adjacent kinomere.

Fibrin Polymerization Defect in HIV-infected Patients-Evidence for a Critical Role of Albumin in the Prolongation of Thrombin and Reptilase Clotting Times

1995 ◽  
Vol 73 (03) ◽  
pp. 349-355 ◽  
Author(s):  
Pierre Toulon ◽  
Elyane Frere ◽  
Claude Bachmeyer ◽  
Nathalie Candia ◽  
Philippe Blanche ◽  
...  
Keyword(s):  
Critical Role ◽  
Human Albumin ◽  
Albumin Level ◽  
Final Concentration ◽  
Albumin Concentration ◽  
Clotting Time ◽  
Fibrin Polymerization ◽  
Small Series ◽  
Group 1

SummaryThrombin clotting time (TCT) and reptilase clotting time (RCT) were found significantly prolonged in a series of 72 HIV-infected patients drawn for routine coagulation testing. Both TCT and RCT were highly significantly correlated with albumin (r = -0.64, and r = -0.73 respectively, p<0.0001). TCT and RCT were significantly higher (p<0.0001) in a series of 30 other HIV-infected patients selected on their albumin level below 30.0 g/l (group l) than in 30 HIV-infected patients with albumin level above 40.0 g/l or in 30 HIV-negative controls; the two latter groups were not different. In vitro supplementation of plasma from group 1 patients with purified human albumin up to 45.0 g/l (final concentration) lead to a dramatic shortening effect on both TCT and RCT, which reached normal values. The TCT and RCT of the purified fibrinogen solutions (2.0 g/l final concentration) were not different in the three groups, and normal polymerization curves were obtained in all cases. This further ruled out the presence of any dysfibrinogenemia in the plasma from group 1 patients. Using purified proteins, highly significant correlations were demonstrated between the albumin concentration and the prolongations of both TCT and RCT, which were of the same magnitude order than those found in the patients plasma. These results suggest that hypo-albuminemia is responsible for the acquired fibrin polymerization defect reported in HIV-infected patients. The pathophysiological implication of the low albumin levels was suggested by the finding of decreased albumin levels (associated with prolonged TCT and RCT) in a small series of the eight HIV-infected patients who developed thrombotic complications.

A New Interpretation of the Structure and Solvent Dependence of the Far UV Circular Dichroism Spectrum of Short Oligopeptides

2019 ◽  
Author(s):  
Anshuman Kumar ◽  
Reinhard Schweitzer-Stenner ◽  
Bryan Wong
Keyword(s):  
Density Functional ◽  
Density Functional Theory Calculations ◽  
Cd Spectra ◽  
Functional Theory ◽  
Polyproline Ii ◽  
Solvent Dependence ◽  
Explicit Consideration ◽  
New Interpretation ◽  
Implicit And Explicit ◽  
Explicit Water

In this work, we carry out new time-dependent density functional theory calculations on the cationic tripeptide GAG in implicit and explicit water to determine the transitions that give rise to the observed CD signals of polyproline II and β-strand conformations. Our results reveal a plethora of electronic transitions that are governed by configurational interactions between multiple molecular orbital transitions of comparable energy. We also show that reproducing the CD spectra of polyproline II and β-strand conformations requires the explicit consideration of water molecules. The structure dependence of delocalized occupied orbitals contributes to the experimentally-observed invalidation of Flory’s isolated pair hypothesis.

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