Editorial [Hot Topic: Proteases as Targets in Medicinal Chemistry (Guest Editor: Dr. Tim F. Tam)]

Protease inhibitors are used to treat and manage a variety of diseases, and have made its mark in drug development. Angiotensin converting enzyme (ACE) inhibitors such as captopril, enalapril, lisinopril, fosinopril, quinapril and ramipril are used to control blood pressure in hypertensive patients. Human immunodeficiency virus (HIV) protease inhibitors, exemplified by amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir are used in treating acquired immunodeficiency syndrome (AIDS). Doxycycline hyclate is the first collagenase inhibitor used for the treatment of periodontal disease. Ximelagatran is a thrombin inhibitor used in venous thrombosis. Broad spectrum inhibitors include camostat mesylate and nafamostat, which help to maintain the pancreatic microcirculation in acute pancreatitis. Clinical applications of protease inhibitors were reviewed in 2005 (Fairlie, D.P.; Abbenante, G. Medicinal Chemistry 2005, 1, 71-104). There is an International Protease Network (www.protease.net) dedicated to protease researchers. This reflects the importance of protease inhibitors as drug candidates for future development. Proteases play an important role in many pathophysiological processes. There are four classes of proteases, categorized by the catalytic residue that effects the hydrolysis of the substrate's amide bond, namely the metallo, aspartic, serine/threonine and cysteine proteases. This special issue gathers reviews on selected protease targets such as matrix metalloprotease, SARSCoronavirus Main protease, cysteine protease, and secretase inhibition. These reviews emphasize the latest developments in synthetic inhibitors, the screening techniques, and the rationale involved in the design of the inhibitors. The first monograph by Amy Sang et al. presents an overview of matrix metalloprotease inhibitors, with particular emphasis on the use of synthetic inhibitors as prospective agents for the prevention and treatment of cardiovascular and neoplastic diseases. Maurizio Pellechia et al. provide an overview of the use of structure- and fragment-based design guided by X-ray crystallography, NMR spectroscopy, computational and/or extended tethering approaches for the identification of potential non-peptidic agents as cysteine and metalloprotease inhibitors. Tanya Schirmeister et al. describe the design of cysteine protease inhibitors with an electrophilic moiety that can covalently bind to the cysteine residue of the active site of the target protease. Examples of such inhibitors are aziridine derivatives and analogues of the diuretic drug, ethacrynic acid. Selective inhibition of cathepsin K has emerged as a potential new therapy for the treatment of osteoporosis. Tae-Seong Kim et al. report the research and development of a series of non-peptidic cathepsin K inhibitors as an alternative to the use of bisphosphonates and anti-RANK ligand therapies. Severe acute respiratory syndrome (SARS) is an emerging infectious disease caused by a novel human coronavirus (CoV). A 3C-like cysteine protease is essential for the life cycle of SARS-CoV. Po-Huang Liang reviews the characterization of SARS-Coronavirus Main protease and various lead inhibitors. This special issue then shifts to the research and development of β- and γ-secretase inhibitors. These two aspartyl proteases cleave amyloid precursor protein to yield amyloid β. Boris Schmidt et al. describe the selective inhibition of both aspartyl proteases, their peptidic and non-peptidic lead inhibitors, and the metabolism of amyloid precursor protein as a potential cause of Alzheimer's disease. Guy Tremblay et al. discuss the importance of tryptase, and chymase in asthma, and the strategies used to inhibit their detrimental action. I would like to thank the authors for their excellent and timely reviews in their respective fields of expertise, and the reviewers for their suggestions and helpful discussions. This special issue is intended to provide the reader with many of the useful concepts and techniques employed in the medicinal chemistry of protease inhibitors. It is not exhaustive, but it provides a concise update for those already familiar with protease research, and an initial reference resource for those wishing to obtain more detailed information on the topic.