Cysteine Proteinase Inhibitors Decrease Articular Cartilage and Bone Destruction in Chronic Inflammatory Arthritis

Abstract

Objective. To determine the effects of peptidyl fluoromethyl ketones on the in vitro activity of purified cathepsins B and L, on tissue cysteine proteinase activity, and on cartilage and bone destruction in experimental arthritis.Methods. The effects of the fluoroketones on cathepsins B and L in vitro and the effects of oral administration of fluoroketones on ex vivo cysteine proteinase activity in tissue homogenates were determined by measuring the inhibition of fluorogenic substrate cleavage. To determine the effects on arthritis, animals were injected with adjuvant or type I1 collagen, treated orally with the fluoroketones, and the severity of arthritis was assessed by clinical, histologic, and radiologic methods.Results. All of the fluoroketones tested were potent inhibitors of purified cathepsins B and L activity.Oral administration of the fluoroketones reduced tissue cysteine proteinase activity by up to 77%. In addition,

Identification and synthesis of a unique thiocarbazate cathepsin L inhibitor

“…A complete biochemical charac-190 terization of this novel chemotype is underway. 31 In summary, samples from the NIH MLSMR revealed promising cathepsin L inhibitory activity attributed to a series of 2,5-disubstituted oxadiazoles (1)(2)(3)(4)(5). Analytical analyses (LC-MS) of the library samples, however, indicated numerous impurities, thus requiring the development of an efficient synthesis for the putative active 2,5-disubstituted oxadiazoles.…”

“…2 For example, cathepsin L is responsible for bone 30 resorption through degradation of collagen type I; this disregulation is believed to lead to osteo-and rheumatoid arthritis. 3 In addition, several infective organisms, such as SARS and Ebola viruses, utilize cathepsin L-like proteins for replication in human cells. 4 The large number of disease states associated with cathepsin L calls for an understanding of the biological function.…”

“…3,7 The few known, potent smallmolecule inhibitors are either peptidic and therefore likely to suffer from physiological instability and poor permeability, or are non-selective for cathepsin L. 3,8,9 The identification of potent, selective, stable, and cell permeable small-molecule inhibitors would therefore be a valuable tool to interrogate cathepsin L and cathepsin L-like function, as well as to provide potential starting points for drug discovery and development. [10][11][12][13][14][15] Initial HTS results of our cathepsin L screen indicated 60 that several structurally related oxadiazoles exhibited potent inhibitory activity (Table 1).…”

Delineating functionally important regions and residues in the cathepsin B propeptide for inhibitory activity

“…However, under conditions where they become deregulated, cysteine proteases are also implicated in a number of degradative and invasive pathological conditions, e.g., arthritis [4,5], tumor invasion and metastasis [6,7] and muscular dystrophy [8]. A number of potent inhibitors of cysteine proteases are available.…”

Role of Cysteine Cathepsins in Joint Inflammation and Destruction in Human Rheumatoid Arthritis and Associated Animal Models

“…Oral administration of a vinyl sulfone cysteine cathepsin-specific inhibitor reduced the signs of inflammation and tissue destruction in this animal model probably by direct local effects and attenuation of MHC-dependent antigen-presentation [88]. Oral administration of fluoromethyl ketones in rats with adjuvant-induced arthritis inhibited at least cysteine cathepsins B and L, and resulted in a reduction of articular cartilage and bone destruction [89]. Adjuvant arthritis can also be investigated in mice.…”