TY  - JOUR
A1  - Bencurova, Elena
A1  - Gupta, Shishir K.
A1  - Sarukhanyan, Edita
A1  - Dandekar, Thomas
T1  - Identification of antifungal targets based on computer modeling
JF  - Journal of Fungi
N2  - Aspergillus fumigatus is a saprophytic, cosmopolitan fungus that attacks patients with a weak immune system. A rational solution against fungal infection aims to manipulate fungal metabolism or to block enzymes essential for Aspergillus survival. Here we discuss and compare different bioinformatics approaches to analyze possible targeting strategies on fungal-unique pathways. For instance, phylogenetic analysis reveals fungal targets, while domain analysis allows us to spot minor differences in protein composition between the host and fungi. Moreover, protein networks between host and fungi can be systematically compared by looking at orthologs and exploiting information from host–pathogen interaction databases. Further data—such as knowledge of a three-dimensional structure, gene expression data, or information from calculated metabolic fluxes—refine the search and rapidly put a focus on the best targets for antimycotics. We analyzed several of the best targets for application to structure-based drug design. Finally, we discuss general advantages and limitations in identification of unique fungal pathways and protein targets when applying bioinformatics tools.
KW  - Aspergillus
KW  - metabolic pathways
KW  - computational modelling
KW  - drug design
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197670
SN  - 2309-608X
VL  - 4
IS  - 3
ER  - 
TY  - JOUR
A1  - Kruse, N.
A1  - Tony, H. P.
A1  - Sebald, Walter
T1  - Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement
N2  - lnterleukin-4 (IL-4) represents a prototypic lymphokine (for a recent review see Paul, 1991). It promotes differentiation of B-cells and the proliferation of T- and B-cell, and other cell types of the lymphoid system. An antagonist of human IL-4 was discovered during the studies presented here after Tyr124 of the recombinant proteinbad been substituted by an aspartic acid residue. This IL-4 variant, Y124D, bound with high affinity to the IL-4 receptor (K\(_D\) = 310 pM), but retained no detectable proliferative activity for T -<:ells and inhibited IL-4-dependent T -cell proliferation competitively (K\(_i\) = 620 pM). The loss of efficacy in variant Y124D was estimated to be > 100-fold on the basis of a weak partial agonist activity for the very sensitive induction of CD23 positive B-cells. The subsitution of Tyr124 by either phenylalanine, histidine, asparagine, Iysine or glycine resulted in partial agonist variants with unaltered receptor binding atTmity and relatively small deficiencies in efficacy. These results demoostrate that high affinity binding and signal generation can be uncoupled efticiently in a Iigand of a receptor betonging to the recently identified hematopoietin receptor family. In addition we show for the first time, that a powerful antagonist acting on the IL-4 receptor system can be derived from the IL-4 protein.
KW  - Biochemie
KW  - drug design
KW  - partial agonists
KW  - receptor signalling
Y1  - 1992
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-62469
ER  -