74 research outputs found
Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Šolaja, B. A. 4-Amino-7-Chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity. Journal of Medicinal Chemistry 2013, 56 (14), 5860–5871. https://doi.org/10.1021/jm4006077
Supporting information for: [https://doi.org/10.1021/jm4006077]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1381
Supplementary data for article: Opsenica, I.; Tot, M.; Gomba, L.; Nuss, J. E.; Sciotti, R. J.; Bavari, S.; Burnett, J. C.; Šolaja, B. A. 4-Amino-7-Chloroquinolines: Probing Ligand Efficiency Provides Botulinum Neurotoxin Serotype A Light Chain Inhibitors with Significant Antiprotozoal Activity. Journal of Medicinal Chemistry 2013, 56 (14), 5860–5871. https://doi.org/10.1021/jm4006077
Supporting information for: [https://doi.org/10.1021/jm4006077]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1381
Supplementary data for article: Opsenica, I.; Burnett, J. C.; Gussio, R.; Opsenica, D. M.; Todorović, N.; Lanteri, C. A.; Sciotti, R. J.; Gettayacamin, M.; Basilico, N.; Taramelli, D.; et al. A Chemotype That Inhibits Three Unrelated Pathogenic Targets: The Botulinum Neurotoxin Serotype A Light Chain, P. Falciparum Malaria, and the Ebola Filovirus. Journal of Medicinal Chemistry 2011, 54 (5), 1157–1169. https://doi.org/10.1021/jm100938u
Supporting information for: [https://doi.org/10.1021/jm100938u]Related to published version: [http://cherry.chem.bg.ac.rs/handle/123456789/1157
Fermi Large Area Telescope Constraints on the Gamma-ray Opacity of the Universe
The Extragalactic Background Light (EBL) includes photons with wavelengths
from ultraviolet to infrared, which are effective at attenuating gamma rays
with energy above ~10 GeV during propagation from sources at cosmological
distances. This results in a redshift- and energy-dependent attenuation of the
gamma-ray flux of extragalactic sources such as blazars and Gamma-Ray Bursts
(GRBs). The Large Area Telescope onboard Fermi detects a sample of gamma-ray
blazars with redshift up to z~3, and GRBs with redshift up to z~4.3. Using
photons above 10 GeV collected by Fermi over more than one year of observations
for these sources, we investigate the effect of gamma-ray flux attenuation by
the EBL. We place upper limits on the gamma-ray opacity of the Universe at
various energies and redshifts, and compare this with predictions from
well-known EBL models. We find that an EBL intensity in the optical-ultraviolet
wavelengths as great as predicted by the "baseline" model of Stecker et al.
(2006) can be ruled out with high confidence.Comment: 42 pages, 12 figures, accepted version (24 Aug.2010) for publication
in ApJ; Contact authors: A. Bouvier, A. Chen, S. Raino, S. Razzaque, A.
Reimer, L.C. Reye
A population of gamma-ray emitting globular clusters seen with the Fermi Large Area Telescope
Globular clusters with their large populations of millisecond pulsars (MSPs)
are believed to be potential emitters of high-energy gamma-ray emission. Our
goal is to constrain the millisecond pulsar populations in globular clusters
from analysis of gamma-ray observations. We use 546 days of continuous
sky-survey observations obtained with the Large Area Telescope aboard the Fermi
Gamma-ray Space Telescope to study the gamma-ray emission towards 13 globular
clusters. Steady point-like high-energy gamma-ray emission has been
significantly detected towards 8 globular clusters. Five of them (47 Tucanae,
Omega Cen, NGC 6388, Terzan 5, and M 28) show hard spectral power indices and clear evidence for an exponential cut-off in the range
1.0-2.6 GeV, which is the characteristic signature of magnetospheric emission
from MSPs. Three of them (M 62, NGC 6440 and NGC 6652) also show hard spectral
indices , however the presence of an exponential cut-off
can not be unambiguously established. Three of them (Omega Cen, NGC 6388, NGC
6652) have no known radio or X-ray MSPs yet still exhibit MSP spectral
properties. From the observed gamma-ray luminosities, we estimate the total
number of MSPs that is expected to be present in these globular clusters. We
show that our estimates of the MSP population correlate with the stellar
encounter rate and we estimate 2600-4700 MSPs in Galactic globular clusters,
commensurate with previous estimates. The observation of high-energy gamma-ray
emission from a globular cluster thus provides a reliable independent method to
assess their millisecond pulsar populations that can be used to make
constraints on the original neutron star X-ray binary population, essential for
understanding the importance of binary systems in slowing the inevitable core
collapse of globular clusters.Comment: Accepted for publication in A&A. Corresponding authors: J.
Kn\"odlseder, N. Webb, B. Pancraz
Iterative Structure-Based Peptide-Like Inhibitor Design against the Botulinum Neurotoxin Serotype A
The botulinum neurotoxin serotype A light chain (BoNT/A LC) protease is the catalytic component responsible for the neuroparalysis that is characteristic of the disease state botulism. Three related peptide-like molecules (PLMs) were designed using previous information from co-crystal structures, synthesized, and assayed for in vitro inhibition against BoNT/A LC. Our results indicate these PLMS are competitive inhibitors of the BoNT/A LC protease and their Ki values are in the nM-range. A co-crystal structure for one of these inhibitors was determined and reveals that the PLM, in accord with the goals of our design strategy, simultaneously involves both ionic interactions via its P1 residue and hydrophobic contacts by means of an aromatic group in the P2′ position. The PLM adopts a helical conformation similar to previously determined co-crystal structures of PLMs, although there are also major differences to these other structures such as contacts with specific BoNT/A LC residues. Our structure further demonstrates the remarkable plasticity of the substrate binding cleft of the BoNT/A LC protease and provides a paradigm for iterative structure-based design and development of BoNT/A LC inhibitors
Gamma-ray and radio properties of six pulsars detected by the fermi large area telescope
We report the detection of pulsed Îł-rays for PSRs J0631+1036, J0659+1414, J0742-2822, J1420-6048, J1509-5850, and J1718-3825 using the Large Area Telescope on board the Fermi Gamma-ray Space Telescope (formerly known as GLAST). Although these six pulsars are diverse in terms of their spin parameters, they share an important feature: their Îł-ray light curves are (at least given the current count statistics) single peaked. For two pulsars, there are hints for a double-peaked structure in the light curves. The shapes of the observed light curves of this group of pulsars are discussed in the light of models for which the emission originates from high up in the magnetosphere. The observed phases of the Îł-ray light curves are, in general, consistent with those predicted by high-altitude models, although we speculate that the Îł-ray emission of PSR J0659+1414, possibly featuring the softest spectrum of all Fermi pulsars coupled with a very low efficiency, arises from relatively low down in the magnetosphere. High-quality radio polarization data are available showing that all but one have a high degree of linear polarization. This allows us to place some constraints on the viewing geometry and aids the comparison of the Îł-ray light curves with high-energy beam models
Second Generation Steroidal 4-Aminoquinolines Are Potent, Dual-Target Inhibitors of the Botulinum Neurotoxin Serotype A Metalloprotease and P. falciparum Malaria
Significantly more potent second generation 4-amino-7-chloroquinoline (4,7-ACQ) based inhibitors of the botulinum neurotoxin serotype A (BoNT/A) light chain were synthesized. Introducing an amino group at the C(3) position of the cholate component markedly increased potency (IC50 values for such derivatives ranged from 0.81 to 2.27 mu M). Two additional subclasses were prepared: bis(steroidal)-4,7-ACQ derivatives and bis(4,7-ACQ)cholate derivatives; both classes provided inhibitors with nanomolar-range potencies (e.g., the K-i of compound 67 is 0.10 mu M). During BoNT/A challenge using primary neurons, select derivatives protected SNAP-25 by up to 89%. Docking simulations were performed to rationalize the compounds' in vitro potencies. In addition to specific residue contacts, coordination of the enzyme's catalytic zinc and expulsion of the enzyme's catalytic water were a consistent theme. With respect to antimalarial activity, the compounds provided better IC90 activities against chloroquine resistant (CQR) malaria than CQ, and seven compounds were more active than mefloquine against CQR strain W2
- …