Protein kinase inhibitors, widely exploited for elucidation of the biological functions of kinases, have more recently come under active consideration as potential chemotherapeutic agents for tumour and other diseases. A brief overview is presented of diverse approaches to the design and development of selective protein kinase inhibitors, and related problems such as donor and acceptor specificities, stereochemical aspects, emerging relationships between protein, sugar and nucleoside kinases. In particular, and contrary to popular belief that ATP-competitive inhibifcrs cannot be selective because of the close homology of the ATP catalytic sites, numerous examples are presented of such inhibitors which are both potent and selective for a given kinase or class of kinases. Some of these are undergoing preclinical trials. Attention is also directed to the role of cellular and viral protein kinases in the ljfe cycle of viruses, and the potential of these enzymes, especially those encoded by, and essential for replication of, a given virus as targets for antiviral chemotherapy.
Insect hemolymph, like vertebrate serum, contains several different types of polypeptides that are able to inhibit the catalytic function of proteolytic enzymes, however studies on proteins possessing this capability have been limited to a relatively few species. A comparative examination of the inhibition of trypsin, chymo- trypsin, neutrophil elastase and cathepsin G and pancreatic elastase by the hemolymph of 14 insect species belonging to six orders showed great diversity in terms of both total proteinase inhibitory capacity and specificity. Most of the inhibitors examined fall into two groups: low molecular mass proteins (below 10 kDa) related to Kunitz type inhibitors, and proteins of about 45 kDa which belong to the serpin superfamily of serine proteinase inhibitors. This minireview describes the properties, characteristics and possible biological significance of selected inhibitors.
The modified nucleotides, N2-(p-n-butylphenyl)dGTP and 2-(p-n-butylanilino) dATP and related compounds have been developed as inhibitor-probes of B family DNA polymerases. Synthetic approaches to these compounds are summarized. The nucleotides are potent, non-substrate inhibitors of DNA polymerase a. In contrast, they inhibit other members of the family with less potency but act as substrates for these enzymes. Modelling of the inhibitor: enzyme binding mechanism has been done based on the known structure of E. coli DNA polymerase I, and site-directed mutagenesis experiments to evaluate this mechanism are proposed.