Development of inhibitors of protein kinases CKI and CKII and some related aspects, including donor and acceptor specificities and viral protein kinases.
A brief overview is presented of progress in the development of specific inhibitors of protein kinases CKI and CKII. Two promising classes of inhibitors, which have the ability to traverse cell membranes, are now known. One of these is based on halogenated benzimidazoles and 2-aza-benzimidazoles (benzotriazoles) and some of their nucleosides. The second embraces modified isoquinoline sulfonamides, several of which are known as inhibitors of other protein kinases. Both classes include analogs that permit discrimination between CKI and CKII. Ongoing research with halogenated benzotriazoles leads to inhibitors with Ki values below 1 microM. Also considered are nucleoside triphosphate analog inhibitors and their potential properties as donors, with illustrative examples from the field of nucleoside kinases, including the apparent existence of a dual-specific viral protein/nucleoside kinase. The role of cellular CKII and viral-encoded CKII-like activities in viral replication underlines the potential of CKII inhibitors as antiviral agents, exemplified by the case of vesicular stomatitis virus.
Shugar
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Institute of Biochemistry & Biophysics, Polish Academy of Sciences, Warszawa.
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology*; D047390:Casein Kinase II; D047388:Casein Kinases; D015195:Drug Design; D005656:Fungal Proteins / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000494:pharmacology*; D015394:Molecular Structure; D010770:Phosphotransferases / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D013552:Swine; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D014982:Xenopus laevis
D000998:Antiviral Agents; D001562:Benzimidazoles; D005656:Fungal Proteins; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D014764:Viral Proteins; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; C021892:nucleoside phosphotransferase; D047390:Casein Kinase II; D047388:Casein Kinases; D017346:Protein Serine-Threonine Kinases