| 1. |
- Johansson, Susanne, et al.
(författare)
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Design, synthesis, and evaluation of N-acyl modified sialic acids as inhibitors of adenoviruses causing epidemic keratoconjunctivitis
- 2009
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 52:12, s. 3666-3678
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Tidskriftsartikel (refereegranskat)abstract
- The adenovirus serotype Ad37 binds to and infects human corneal epithelial (HCE) cells through attachment to cellular glycoproteins carrying terminal sialic acids. By use of the crystallographic structure of the sialic acid-interacting domain of the Ad37 fiber protein in complex with sialyllactose, a set of N-acyl modified sialic acids were designed to improve binding affinity through increased hydrophobic interactions. These N-acyl modified sialic acids and their corresponding multivalent human serum albumin (HSA) conjugates were synthesized and tested in Ad37 cell binding and cell infectivity assays. Compounds bearing small substituents were as effective inhibitors as sialic acid. X-ray crystallography and overlays with the Ad37-sialyllactose complex showed that the N-acyl modified sialic acids were positioned in the same orientation as sialic acid. Their multivalent counterparts achieved a strong multivalency effect and were more effective to prevent infection than the monomers. Unfortunately, they were less active as inhibitors than multivalent sialic acid.
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| 3. |
- Nordfelth, R., et al.
(författare)
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Small-molecule inhibitors specifically targeting type III secretion
- 2005
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Ingår i: Infection and Immunity. - Washington : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 73:5, s. 3104-3114
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Tidskriftsartikel (refereegranskat)abstract
- The type III secretion (TTS) system is used by several animal and plant pathogens to deliver effector proteins into the cytosol of the eukaryotic target cell as a strategy to evade the defense reactions elicited by the infected organism. The fact that these systems are highly homologous implies that novel antibacterial agents that chemically attenuate the pathogens via a specific interaction with the type III secretion mechanism can be identified. A number of small organic molecules having this potential have recently been identified (A. M. Kauppi, R. Nordfelth, H. Uvell, H. Wolf-Watz, and M. Elofsson, Chem. Biol. 10:241-249, 2003). Using different reporter gene constructs, we showed that compounds that belong to a class of acylated hydrazones of different salicylaldehydes target the TTS system of Yersinia pseudotuberculosis. One of these compounds, compound 1, was studied in detail and was found to specifically block Yop effector secretion under in vitro conditions by targeting the TTS system. In this respect the drug mimics the well-known effect of calcium on Yop secretion. In addition, compound I inhibits Yop effector translocation after infection of HeLa cells without affecting the eukaryotic cells or the bacteria. A HeLa cell model that mimics in vivo conditions showed that compound 1 chemically attenuates the pathogen to the advantage of the eukaryotic cell. Thus, our results show proof of concept, i.e., that small compounds targeting the TTS system can be identified, and they point to the possible use of TTS inhibitors as a novel class of antibacterial agents.
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