| 1. |
- Kauppi, Anna, 1971-, et al.
(författare)
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Targeting bacterial Virulence : Inhibitors of type III secretion in Yersinia
- 2003
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Ingår i: Chemistry and Biology. - 1074-5521 .- 1879-1301. ; 10:3, s. 241-249
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Tidskriftsartikel (refereegranskat)abstract
- Agents that target bacterial virulence without detrimental effect on bacterial growth are useful chemical probes for studies of virulence and potential candidates for drug development. Several gram-negative pathogens employ type III secretion to evade the innate immune response of the host. Screening of a chemical library with a luciferase reporter gene assay in viable Yersinia pseudotuberculosis furnished several compounds that inhibit the reporter gene signal expressed from the yopE promoter and effector protein secretion at concentrations with no or modest effect on bacterial growth. The selectivity patterns observed for inhibition of various reporter gene strains indicate that the compounds target the type III secretion machinery at different levels. Identification of this set of inhibitors illustrates the approach of utilizing cell-based assays to identify compounds that affect complex bacterial virulence systems.
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| 2. |
- Tjernberg, L O, et al.
(författare)
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Amyloid beta-peptide polymerization studied using fluorescence correlation spectroscopy
- 1999
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Ingår i: Chemistry and Biology. - 1074-5521 .- 1879-1301. ; 6:1, s. 53-62
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Tidskriftsartikel (refereegranskat)abstract
- Background: The accumulation of fibrillar deposits of amyloid beta-peptide (A beta) in brain parenchyma and cerebromeningeal blood vessels is a key step in the pathogenesis of Alzheimer's disease. In this report, polymerization of A beta was studied using fluorescence correlation spectroscopy (FCS), a technique capable of detecting small molecules and large aggregates simultaneously in solution. Results: The polymerization of A beta dissolved in Tris-buffered saline, pH 7.4, occurred above a critical concentration of 50 mu M and proceeded from monomers/dimers into two discrete populations of large aggregates, without any detectable amount of oligomers. The aggregation showed very high cooperativity and reached a maximum after 40 min, followed by an increase in the amount of monomers/dimers and a decrease in the size of the large aggregates. Electron micrographs of samples prepared at the time for maximum aggregation showed a mixture of an amorphous network and short diffuse fibrils, whereas only mature amyloid fibrils were detected after one day of incubation. The aggregation was reduced when A beta was incubated in the presence of A beta ligands, oligopeptides previously shown to inhibit fibril formation, and aggregates were partly dissociated after the addition of the ligands. Conclusions: The polymerization of A beta is a highly cooperative process in which the formation of very large aggregates precedes the formation of fibrils. The entire process can be inhibited and, at least in early stages, partly reversed by A beta ligands.
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| 3. |
- Andersson, Emma K., et al.
(författare)
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Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones
- 2013
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Ingår i: Chemistry and Biology. - : Elsevier. - 1074-5521 .- 1879-1301. ; 20:10, s. 1245-1254
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Tidskriftsartikel (refereegranskat)abstract
- Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."
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| 4. |
- Andersson, Emma K., et al.
(författare)
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Small Molecule Disruption of B-subtilis Biofilms by Targeting the Amyloid Matrix
- 2013
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Ingår i: Chemistry and Biology. - : Cell Press. - 1074-5521 .- 1879-1301. ; 20:1, s. 5-7
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Small molecule inhibitors of amyloid aggregation have potential as treatment for a variety of conditions. In this issue of Chemistry & Biology, Romero and colleagues use amyloid-dependent B. subtilis biofilm formation to screen for amyloid inhibitors, identifying compounds that not only inhibit B. subtilis biofilm formation but also ones that disrupt preformed biofilms.
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| 5. |
- Andersson, Theresa, et al.
(författare)
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The binding of human Carbonic Anhydrase II by functionalized folded polypeptide receptors
- 2005
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Ingår i: Chemistry and Biology. - : Elsevier BV. - 1074-5521 .- 1879-1301. ; 12:11, s. 1245-1252
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Tidskriftsartikel (refereegranskat)abstract
- Several receptors for human carbonic anhydrase II (HCAII) have been prepared by covalently attaching benzenesulfonamide carboxylates via aliphatic aminocarboxylic acid spacers of variable length to the side chain of a lysine residue in a designed 42 residue helix-loop-helix motif. The sulfonamide group binds to the active site zinc ion of human carbonic anhydrase II located in a 15 Å deep cleft. The dissociation constants of the receptor-HCAII complexes were found to be in the range from low micromolar to better than 20 nM, with the lowest affinities found for spacers with less than five methylene groups and the highest affinity found for the spacer with seven methylene groups. The results suggest that the binding is a cooperative event in which both the sulfonamide residue and the helix-loop-helix motif contribute to the overall affinity.
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| 6. |
- Anscombe, Elizabeth, et al.
(författare)
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Identification and Characterization of an Irreversible Inhibitor of CDK2
- 2015
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Ingår i: Chemistry and Biology. - : Elsevier BV. - 1074-5521 .- 1879-1301. ; 22:9, s. 1159-1164
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Tidskriftsartikel (refereegranskat)abstract
- Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclo-hexylmethoxy)-9H-purin-2-yl) amino) benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl) phenyl)-9H- purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.
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| 7. |
- Braesel, Jana, et al.
(författare)
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Three Redundant Synthetases Secure Redox-Active Pigment Production in the Basidiomycete Paxillus involutus.
- 2015
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Ingår i: Chemistry and Biology. - : Elsevier BV. - 1879-1301 .- 1074-5521. ; 22:10, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- The symbiotic fungus Paxillus involutus serves a critical role in maintaining forest ecosystems, which are carbon sinks of global importance. P. involutus produces involutin and other 2,5-diarylcyclopentenone pigments that presumably assist in the oxidative degradation of lignocellulose via Fenton chemistry. Their precise biosynthetic pathways, however, remain obscure. Using a combination of biochemical, genetic, and transcriptomic analyses, in addition to stable-isotope labeling with synthetic precursors, we show that atromentin is the key intermediate. Atromentin is made by tridomain synthetases of high similarity: InvA1, InvA2, and InvA5. An inactive atromentin synthetase, InvA3, gained activity after a domain swap that replaced its native thioesterase domain with that of InvA5. The found degree of multiplex biosynthetic capacity is unprecedented with fungi, and highlights the great importance of the metabolite for the producer.
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| 8. |
- Doak, Bradley Croy, et al.
(författare)
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Oral Druggable Space beyond the Rule of 5 : Insights from Drugs and Clinical Candidates
- 2014
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Ingår i: Chemistry and Biology. - : Elsevier BV. - 1074-5521 .- 1879-1301. ; 21:9, s. 1115-1142
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Forskningsöversikt (refereegranskat)abstract
- The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets.
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| 9. |
- Haeggstrom, JZ, et al.
(författare)
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Resolving resolvins
- 2013
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Ingår i: Chemistry & biology. - : Elsevier BV. - 1879-1301 .- 1074-5521. ; 20:2, s. 138-140
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Tidskriftsartikel (refereegranskat)
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| 10. |
- Hansson, Magnus, et al.
(författare)
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Bioengineering and Semisynthesis of an Optimized Cyclophilin Inhibitor for Treatment of Chronic Viral Infection.
- 2015
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Ingår i: Chemistry and Biology. - : Elsevier BV. - 1879-1301 .- 1074-5521. ; 22:2, s. 285-292
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of host-encoded targets, such as the cyclophilins, provides an opportunity to generate potent high barrier to resistance antivirals for the treatment of a broad range of viral diseases. However, many host-targeted agents are natural products, which can be difficult to optimize using synthetic chemistry alone. We describe the orthogonal combination of bioengineering and semisynthetic chemistry to optimize the drug-like properties of sanglifehrin A, a known cyclophilin inhibitor of mixed nonribosomal peptide/polyketide origin, to generate the drug candidate NVP018 (formerly BC556). NVP018 is a potent inhibitor of hepatitis B virus, hepatitis C virus (HCV), and HIV-1 replication, shows minimal inhibition of major drug transporters, and has a high barrier to generation of both HCV and HIV-1 resistance.
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