ABSTRACT
There is today a blatant need for new antifungal agents, because of the recent increase in life-threatening infections involving an ever-greater number of fungal strains. Fungi make extensive use of kinases in the regulation of essential processes, in particular the cell cycle. Most fungal kinases, however, are shared with higher eukaryotes. Only the kinases which have no human homologs, such as the histidine kinases, can be used as targets for antifungal drugs design. This review describes efforts directed towards the discovery of drugs active against a novel target, the atypical cell cycle kinase, Civ1.
Subject(s)
Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Cyclin-Dependent Kinases , Protein Serine-Threonine Kinases/antagonists & inhibitors , Purines/chemistry , Purines/pharmacology , Amino Acid Sequence , Cell Cycle Proteins/antagonists & inhibitors , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fungal Proteins/antagonists & inhibitors , Fungi/drug effects , Fungi/enzymology , Fungi/physiology , Models, Molecular , Molecular Sequence Data , Structure-Activity Relationship , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
Life-threatening fungal infections are becoming more frequent and involve a greater variety of strains, many of which are drug-resistant. Both public research organisations and the pharmaceutical industry are committed to the development of new drugs to satisfy this increasing medical need. The approach described here exemplifies the efforts directed towards the discovery of drugs which are active against novel targets, exemplified by the cell-cycle regulator, Civ1.
Subject(s)
Antifungal Agents/pharmacology , Cell Cycle Proteins/drug effects , Cyclin-Dependent Kinases , Fungi/drug effects , Fungi/enzymology , Mycoses/drug therapy , Mycoses/enzymology , Animals , Cell Cycle Proteins/metabolism , Drug Evaluation, Preclinical , Drug Resistance, Fungal/drug effects , Drug Resistance, Fungal/physiology , Fungi/pathogenicity , Humans , Molecular Structure , Mycoses/physiopathology , Protein Serine-Threonine Kinases/drug effects , Protein Serine-Threonine Kinases/metabolism , Sequence Homology, Amino Acid , Cyclin-Dependent Kinase-Activating KinaseABSTRACT
Protein kinases (Ser/Thr and Tyr) play a key role in signal transduction pathways. It has been shown that deregulation of the Cdk activity is linked to cell proliferation and cancer. Inhibition of cyclin-dependent kinases (Cdks) is an important target for potential new anti-cancer drugs. Following the discovery of Olomoucine, a wide range of tri-substituted purine derivatives have been synthesized, leading to potent Cdk inhibitors. These purine-derived compounds bind to the ATP pocket of the protein. Of interest for structure-based drug design, the different crystal structures published to date show evidence for three different binding modes for the purine ring, allowing diverse exploration of the ATP binding site. Some examples of synthesis and structure activity relationships are discussed for a set of purine derivatives, tri-substituted on C-2, N-9 and C-6. Finally, in vivo activities are reviewed, as well as the applications in other therapeutic areas.
