ABSTRACT
The nucleotide (nt) sequences of two closely related isolates (CeWF-2 and CeWGH-2) of a novel tobacco rattle virus (TRV) RNA2 were determined. The sequences of their RNA2-specific regions were almost identical and contained four open reading frames (ORFs) in an arrangement similar to that found in the previously described TRV TpO1 RNA2. Their predicted ORF 1 gene products shared 97 % amino acid sequence identity with the TpO1 coat protein, but the ORF 2 and ORF 3 gene products shared only 82 % sequence identity, and no appreciable sequence similarity was found between the CeWF-2/CeWGH-2 and TpO1 ORF 4 gene products. In the CeWGH-2 sequence, the RNA2-specific and RNA1-related regions were separated by seven adenine (A) residues. In CeWF-2, however, an internal poly(A) tract (IPAT) of variable size consisting of ca. 20 to 30 (A) residues was found. This is the first report of an IPAT occurring in a tobravirus RNA2.
Subject(s)
DNA, Intergenic , Poly A/genetics , RNA Viruses/genetics , RNA, Viral/genetics , Solanum tuberosum/virology , Gene Order , Genome, Viral , Open Reading Frames , RNA Viruses/isolation & purification , Sequence Analysis, DNA , Sequence Homology, Amino AcidABSTRACT
So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3ß, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.
Subject(s)
Alzheimer Disease/enzymology , Enzyme Inhibitors/chemistry , Glycogen Synthase Kinase 3 beta/metabolism , tau Proteins/metabolism , Alzheimer Disease/drug therapy , Animals , COS Cells , Chlorocebus aethiops , Drug Discovery , Enzyme Inhibitors/pharmacology , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , Mitogen-Activated Protein Kinase 6/metabolism , Phosphorylation/drug effects , Transfection , tau Proteins/drug effectsABSTRACT
The almost complete nucleotide sequences lacking only the short primer-derived 5' and 3' ends were determined for two closely related isolates of a new tobacco rattle virus (TRV) RNA2, i.e., ByKT (Bav)-2 and ByKT (LS)-2. These isolates originated from corky-ringspot-affected potato-growing areas in southern Germany (Bavaria) and northern central Germany (Lower Saxony), respectively, where they were associated with distinct supporting TRV RNA1s. In potatoes in other parts of Germany, TRV RNA2s closely related to TRV TpO1 RNA2 were identified. They, too, were associated with distinct TRV RNA1s in different parts of the country.
