PACE4 – A Novel Therapeutic Drug Target for Osteoarthritis

Author Name(s): Ashwathi Arya M
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Osteoarthritis (OA) is a degenerative joint disease which occurs mainly due to aging and mechanical stress. So far only temporary methods like giving pain alleviating drugs are employed for the treatment of OA but a permanent solution to cure the disease has not yet been established. The need of the hour is to find this permanent solution and completely undo the disease. The current work is on Computer Aided Drug Designing against Osteoarthritis. PACE4, a pro protein convertase involved in aggrecanase activation in cartilage is a major protein responsible for the occurrence of this disease. Therefore targeting PACE4 can be an effective therapy. The sequence, structure and functional analysis were performed using various insilico tools. The target site on the receptor protein was selected based on the analysis of mutational sites and the presence of the binding site among the selected mutational site. The potential chemical compounds which could be used for the treatment were screened for drug likeliness, toxicity and ambiguity. The binding affinity between the receptor protein and final screened chemical ligands were analyzed by performing Docking studies. Based on Binding affinity it was shown that the chemical compound named Calpain Inhibitor I was found to be the best drug ligand acting against the targeted PACE4 protein. Thus our studies support that Calpain Inhibitor I can be used as a potent drug candidate for the treatment of Osteoarthritis.


Osteoarthritis is a chronic degenerative disorder of multifactorial etiology characterized by loss of articular cartilage, hypertrophy of bone at the margins, subchondral sclerosis and range of biochemical and morphological alterations of the synovial membrane and joint capsule [1]. OA is best considered as a disease of the whole “joint organ”. Medical conditions that can lead to OA involve bleeding disorders that cause bleeding in the joint such as hemophilia, disorders that block the blood supply near a joint and lead to a vascular necrosis and other types of arthritis, such as chronic gout, pseudo gout, or rheumatoid arthritis[2][3]. Proteolytic degradation of the major cartilage macromolecules, aggrecan and type II collagen, is a key pathological event in OA[4]. The particular chondrocytes are able to maintain the phenotypic characteristics of the tissue such as resistance to mineralization and vascular invasion. However, when challenged in the onset and progression of osteoarthritis not only are these cells activated and increase matrix molecule synthesis, but they also produce pro inflammatory cytokines and tissue-destructive enzymes. The catabolic processes gradually outmatch anabolic efforts, resulting in progressive degradation of the cartilage [5][6]. ADAMTS-4 and ADAMTS-5, the primary aggrecanases capable of cartilage aggrecan cleavage, are synthesized as latent enzymes and require prodomain removal for activity. The N-termini of the mature proteases suggest that activation involves a pro protein convertase, but the specific family member responsible for aggrecanase activation in cartilage in situ has not been identified. PACE4 was identified as a pro protein convertase responsible for activation of aggrecanases in osteoarthritic and cytokine-stimulated cartilage. Posttranslational activation of ADAMTS-4 and ADAMTS-5 in the extracellular milieu of cartilage results in aggrecan degradation [7]. These findings suggest that PACE4 represents a novel target for the development of OA therapeutics.


In light of Pace4 receptor protein being an aggrecanase stimulator, it serves as a therapeutic target in Osteoarthritis. When Pace4 is docked, it will cease to act as an aggrecanase stimulator which in turn will prevent the aggrecanases from acting on aggrecan, a major cartilage macromolecule. This process can avert proteolytic` degradation to a major extent and thereby block the progression of Osteoarthritis. Out of the ten compounds that were docked with Pace4 receptor in Hex, Calpain Inhibitor I showed the least docking energy and thus can be considered as the most acceptable drug candidate having the best binding affinity with the Pace4 receptor. The study can be promising if followed by clinical study.

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