CTSS

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Introduction

Due to restricted tissue expression, cathepsin S is unique in the cysteine cathepsin family and is associated with antigen-presenting cells located in the lymph and spleen and other immune cells. At the same time, the ability of cathepsin S to maintain strong stability at neutral pH is also different from many other family members, which also reflects its increased potential to participate in extracellular proteolytic activities. Therefore, these characteristics highlight the potential of cathepsin S as an ideal target for disease treatment. Due to its highly restricted expression, therapeutic inhibition should minimize potential side effects.

Human cathepsin S is produced by its cognate CTSS gene located on chromosome 1q21. First, a pre-proenzyme with a length of 331 amino acids is synthesized, including a signal domain, a pro-peptide domain, and a mature domain with lengths of 16, 98, and 217 amino acids, respectively. Studies in mouse models have found that mice lacking the Ctss gene exhibit reduced MHC class II (MHCII) antigen presentation. MHCII antigen presentation requires the presence of the type II glycoprotein invariant chain (li; CD74). After reaching the endo-lysosomal pathway in the antigen-presenting cell, the invariant chain is removed from the MHCII complex to allow subsequent antigen loading. In this process, the removal of invariant proteins is mediated by several discrete proteolytic cleavages, including cathepsin S.

Cathepsin S and disease

Like many other proteases, more and more studies have reported the association of cathepsin S with a range of substrates and pathological conditions. With the development of chemical biology probes and substrates, gene ablation models, and as well as other tools, the role of cathepsin S in these diseases has been more comprehensively analyzed, highlighting its powerful potential as a therapeutic target. Cathepsin S can recognize a variety of intracellular and extracellular substrates, including CD74 involved in major histocompatibility complex class II (MHCII), E-cadherin involved in intracellular adhesion, Protease-activated receptor-2 (PAR-2) involved in pain signaling, secretory leukocyte protease inhibitor (SLPI), junctional adhesion molecule-B (JAM-B) involved in cathepsin S derived blood brain barrier metastases, and collagen/elastin that constitutes the extracellular matrix and basement membrane structure.

Since cathepsin S is a protein that responds to inflammatory stimuli, this protease has always been considered a target for immune diseases. Inhalation of allergens in asthma patients can stimulate the recruitment of inflammatory cells to the lungs. Due to the role of CTSS in the antigen presentation pathway, it may contribute to the research progress of asthma pathology. The overall maintenance of many cardiovascular diseases is driven by a protease: anti-protease balance. Although MMPs have been widely studied, cathepsin S has become an important participant in the pathogenesis of a series of cardiovascular diseases (such as atherosclerosis and abdominal aortic aneurysm, etc.).

Figure 1. Substrates of cathepsin S (Wilkinson, R.D.A.; et al. 2015)

The therapeutic utility of cathepsin S

Researchers' interest in cathepsin S as a target has greatly promoted the development of a wide range of low molecular weight, small molecule compounds. These compounds bind to the active site of the target protease and bind to catalytic cysteine residues via the employment of a warhead that is typically electrophilic in nature. At present, the complex structure of cathepsin S: inhibitor complex determined by X-ray crystallography has been obtained. From this three-dimensional structure, the substrate binding cleft at the active site of the protease can be analyzed in detail to develop selective cathepsin inhibitors.

Cathepsin inhibitors can cause problems with the accumulation of weakly basic and lipophilic compounds in the lysosomal compartment of the cell. Such a situation will increase the off-target binding of the inhibitor, thereby reducing its efficacy. Through continuous efforts, the progress of cathepsin K compound lysomotrophism problem opened up the potential to target other cathepsins (such as cathepsin S). Cathepsin S inhibitor LY3000328 has recently completed phase I clinical trials, and several cathepsin S inhibitors are undergoing clinical trials for the treatment of psoriasis, rheumatoid arthritis, and neuropathic pain. The critical role of cathepsin S in a large number of inflammatory diseases and tumorigenesis is likely to further accelerate the process of clinical evaluation of cathepsin S compounds.

Table 1. Cathepsin inhibitors currently undergoing clinical trials (Wilkinson, R.D.A.; et al. 2015)