Editorial [Hot Topic: Recent Advances and Future Prospect in Protease Targeting (Executive Editor: B. Turk) ]

Proteases have been known for many years as protein-degrading enzymes. However, this view has dramatically changed and proteases are now considered as extremely important signalling molecules, involved in numerous vital processes. Their activity requires strict regulation and regulation defects can lead to pathologies, often associated with excessive proteolysis. The number of diseases, where proteases were identified to be important, if not essential, is increasing almost exponentially and proteases are therefore seriously considered as important drug targets in the areas of cardiovascular diseases, cancer, neurodegenerative diseases (Alzheimer, ...), osteoporosis, diabetes type II, pancreatitis, inflammation, arthritis and rheumatoid arthritis, to list just some of them. In addition, there has been a boom also in the area of infectious diseases, which were less seriously considered with few exceptions such as AIDS and hepatitis C. The recent determination of human, mouse, monkey and rat genomes, as well as the development of new technologies set new standards for more rapid target identification and validation, which is reflected also in the protease field. The major progress in the field resulted in successful development of drugs targeting new targets, such as dipeptidyl peptidase IV inhibitors (Novartis, Merck) for diabetes type II and a renin inhibitor for hypertension (Novartis), which are expected to be launched in 2007. Moreover, the number of new compounds being currently tested in advanced clinical trials suggests a major increase of new therapies based on protease inhibition in the coming years, which is also expected to largely increase the current ∼$11 billion market for protease-targeted drugs [1]. The goal of this issue, which is divided into two parts, is to review some of the current advances in the field. The first part contains 6 papers ([2-7], whereas the last four papers are in the second part of this issue [8-11]]. In the first paper, Fonovi and Bogyo describe development of activity based probes for proteases, and their applications to biomarker discovery, molecular imaging and drug screening [2]. In the next paper, Butler and Overall describe the power of proteomics in validation of protease drug targets, illustrated on an example from metalloprotease inhibition [3]. This is followed by a paper from Eder et al. [4], who describe the development of inhibitors against different aspartic proteases, including the development of renin inhibitors, where an NDA has been filed in this year. Prezeljz et al. discuss the recent advances in anticoagulant therapy based on the inhibition of serine protease inhibition [5]. In another paper based on serine proteases, Sommerhoff and Schaschke describe current advances in the development of tryptase inhibitors for treatment of allergic diseases, including bronchial asthma [6]. After the failure of broad spectrum MMP inhibitors in cancer and rheumatoid arthritis, the focus of MMP inhibition has shifted as described by Fingleton [7] in the last paper of the first part. In addition to MMPs, also metalloprotease exopeptidases can be attractive targets, as described by Arolas et al. [8] in the first paper of the second part. There are also important targets among cysteine proteases, as shown by the papers on caspase [9] and cysteine cathepsin [10] inhibition, where the compounds have also progressed into the clinical studies. Finally, the issue is concluded by a paper from Kido et al. on development of drugs against human influenza virus based on protease inhibition [11]. At the end, I would like to thank all the authors for their contributions, as well as Mr. Mirza Kazim Ali Baig from Bentham Science Publishers for all his help and support. References [1] Turk B. Targeting proteases: successes, failures and future prospects. Nat Rev Drug Disc 2006; 5: 785-99. [2] Fonovi M, Bogyo M. Activity based probes for proteases: applications to biomarker discovery, molecular imaging and drug screening. Curr Pharm Des 2007; 13(3): 253-261. [3] Butler GS, Overall CM. Proteomic validation of protease drug targets. Curr Pharm Des 2007; 13(3): 263-270. [4] Eder J, Hommel U, Cumin F, Martoglio B, Gerhartz B. Aspartic proteases in drug discovery. Curr Pharm Des 2007; 13(3): 271-285.........